JP2019172682A - Pharmaceutical compositions comprising nitroxyl donors - Google Patents

Abstract

【選択図】なしDisclosed is a composition containing a nitroxyl-donating compound used for parenteral administration for treating heart failure, the composition having sufficient solubility and stability.
An N-hydroxysulfonamide-type nitroxyl-donating compound represented by the formula (1) and a sulfo-n-butyl ether of β-cyclodextrin having 6 or 7 sulfo-n-butyl ether groups per molecule. A pharmaceutical composition suitable for intravenous administration comprising a derivative and an aqueous buffer and having a pH of about 5 to about 6.

[Selection figure] None

Description

[Background technology]
Nitroxyl (HNO) has been shown to have positive cardiovascular effects in in vitro and in vivo models of failing hearts. However, at physiological pH, HNO dimerizes to hyponitrous acid and subsequently dehydrates to nitrous oxide. Because of this metastability, HNO for therapeutic use must be generated from the donor compound in situ. Various compounds that can donate nitroxyl have been described and have been proposed for use in treating disorders known or likely to respond to nitroxyl. For example, U.S. Patent Nos. 6,936,639, 7,696,373, 8,030,356, 8,268,890, 8,227,639, and No. 8,318,705 and U.S. pre-grant publications 2009/0281067, 2009/0298795, 2011/0136827, and 2011/0144067. All of these compounds can donate nitroxyl, but there are differences in various physicochemical properties and nitroxyl donation still has optimal physicochemical properties to treat a particular clinical condition by a particular route of administration I need to identify my body.

  US Pat. No. 8,030,056 describes derivatives of pyrotic acid-type compounds that can be fed nitroxyl under physiological conditions and are useful in treating heart failure and ischemia / reperfusion injury. A synthesis is described. The nitroxyl donor CXL-1020 (N-hydroxy-2-methanesulfonylbenzene-1-sulfonamide) is a Phase I safety study in healthy volunteers, conducted in a number of hospitals, and Phase IIa It was evaluated in a placebo-controlled double-blind dose escalation study. Sabbah et al., “Nitroxyl (HNO) a novel approach for the acute treatment of heart failure”, Circ Heart Fail., Published online October 9, 2013 (Online ISSN: 1941-3297, Print ISSN: 1941-3289). According to this study, in patients with systolic heart failure, CXL-1020 improved both the cardiac index and stroke volume coefficient when administered intravenously as a pH = 4 aqueous solution, while increasing both left and right heart filling pressures. As well as reducing total peripheral vascular resistance. Thus, this study demonstrated that CXL-1020 enhanced myocardial function in human patients suffering from heart failure. However, at the threshold dose of CXL-1020 required to produce hemodynamic effects, this compound may induce side effects including unacceptable levels of inflammatory stimuli at the intravenous insertion site and its distal portion. The authors report that because of these side effects, this compound would not be a viable candidate for human therapeutics.

  Accordingly, there is a need to develop new nitroxyl donor compounds (referred to herein as nitroxyl donors) and compositions that are useful in the treatment of heart failure and have an appropriate toxicological profile. The development of such compounds requires an understanding of the pharmacokinetic profile associated with nitroxyl donation and the factors that affect the toxicological profile. The inability to understand these factors has hindered the development of nitroxyl donors for clinical use.

  Furthermore, formulation of nitroxyl donors has proven to be a significant challenge. Many current nitroxyl donors are insoluble in aqueous solutions and / or have poor stability. Solubility and stability issues often preclude the use of such compounds in pharmaceutical compositions for parenteral and / or oral administration. Accordingly, a composition containing a nitroxyl donor at a concentration sufficient for parenteral and / or oral administration, which is sufficiently stable and has an advantageous pharmacological and toxicological profile. There is a need to develop.

  Citation of any reference in Section 1 of this application should not be construed as an admission that such reference is prior art to the present application.

  The present disclosure is highly effective in treating cardiovascular diseases (eg, heart failure), has a suitable toxicological profile, and is sufficiently stable for intravenous or oral administration It relates to the discovery of compositions.

  Under physiological conditions, the toxicological profile of an N-hydroxysulfonamide type nitroxyl donor having a sufficiently long half-life is the N-hydroxysulfonamide type nitroxyl donor having a shorter half-life (eg, CXL-1020). ) Was found to be significantly better than the toxicological profile. In particular, as measured in aerated phosphate buffered saline (PBS) pH 7.4 or in plasma (eg, human plasma) according to the procedure described in Example 2 (in section 5.2). It has been discovered that N-hydroxysulfonamide type nitroxyl donors with short half-lives (ie, less than 10 minutes) have undesirable toxicity when administered parenterally (eg intravenously). The term “N-hydroxysulfonamide type nitroxyl donor” includes compounds having a free sulfonamide hydroxyl group (eg, the compounds illustrated in Tables 1 and 2 of Section 4.2), as illustrated below. A compound in which the N-hydroxy group of sulfonamide is esterified

（式中、

(Where

は、本化合物の芳香族性、複素芳香族性または多環式部分を表す（Ｒの定義に関しては、セクション４．２を参照されたい））
の両方が含まれることが理解されよう。

Represents an aromatic, heteroaromatic or polycyclic moiety of the compound (see section 4.2 for definition of R)
It will be understood that both are included.

  According to the present disclosure, N-hydroxysulfonamide type nitroxyl donors having a half-life greater than 10 minutes, as measured in PBS or human plasma, have a high level of efficacy in the treatment of cardiovascular disease (eg, heart failure). And a significant improvement in toxicological profile compared to N-hydroxysulfonamide type nitroxyl donors such as CXL-1020, which have a half-life of less than 10 minutes.

  In certain embodiments, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of the present disclosure (ie, nitroxyl donating compositions) is pH 7.4 under the conditions specified in Example 2. Has a half-life of greater than 10 minutes when measured in an aerated phosphate buffered saline (PBS) solution. In certain embodiments, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure are measured in aerated PBS solution at pH 7.4 under the conditions specified in Example 2. It has a half-life of about 12 minutes to about 150 minutes. In a specific embodiment, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical composition of the present disclosure is measured in aerated PBS solution at pH 7.4 under the conditions specified in Example 2. Has a half-life of about 15 minutes to about 70 minutes. Specific examples of such compounds of the present disclosure are listed in Tables 1 and 2 (see Section 4.2).

  In certain embodiments, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of the present disclosure is an anticoagulant (eg, heparin or sodium citrate) under the conditions specified in Example 2. Has a half-life of greater than 10 minutes when measured in human plasma at pH 7.4. In certain embodiments, an N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of this disclosure is 10 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. Has a half-life of greater than about 85 minutes. In some embodiments, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of the present disclosure is approximately about 7.4 when measured in human plasma at pH 7.4 under the conditions specified in Example 2. It has a half-life of 12 minutes to about 85 minutes. In certain embodiments, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure are about 25 as measured in human plasma at pH 7.4 under the conditions specified in Example 2. Has a half-life of about 75 minutes to about 75 minutes. Specific examples of such compounds of the present disclosure are listed in Tables 1 and 2.

  In certain embodiments, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of the present disclosure is a compound of formula (1)

である。

It is.

  In another embodiment, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of this disclosure is a compound of formula (2)

である。

It is.

  Compositions containing N-hydroxysulfonamide type nitroxyl donors formulated at a pH of about 5 or higher are at more acidic pH levels, such as CXL-1020 compositions evaluated in Phase I and Phase IIa clinical trials. It was further discovered that it has a significantly improved toxicological profile compared to a composition comprising a formulated N-hydroxysulfonamide type nitroxyl donor. Thus, in various embodiments, the N-hydroxysulfonamide type nitroxyl donor can be formulated for parenteral injection at a pH of about 5 to about 6 (eg, a pH of about 5, about 5.5 or about 6). . Formulation within this pH range reduces undesirable potential side effects (eg, reduces venous irritation) compared to more acidic compositions. Surprisingly, formulation of N-hydroxysulfonamide type nitroxyl donors can be achieved at a pH in the range of about 5 to about 6 without adversely affecting the stability of the nitroxyl donor.

  Furthermore, it has been discovered that certain additives can be used to stabilize and / or solubilize nitroxyl donors useful in the disclosed compositions. In various embodiments, at least one such pharmaceutically acceptable additive comprises at least one cyclodextrin species. In one such embodiment, the additive is β-cyclodextrin. One preferred β-cyclodextrin is CAPTISOL®.

  In embodiments where a cyclodextrin (eg, CAPTISOL®) acts as an additive in the disclosed pharmaceutical composition, the amount of cyclodextrin in the composition is dependent on the solubility and / or stability of the nitroxyl donor. It will depend on sex. For example, the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and cyclodextrin present in the composition can be from about 0.02: 1 to about 2: 1. In certain embodiments, the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and cyclodextrin present in the composition can be from about 0.05: 1 to about 1.5: 1. . In certain embodiments, the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and cyclodextrin present in the composition can be from about 0.1: 1 to about 1: 1. In certain embodiments, the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and cyclodextrin present in the composition can be from about 0.5: 1 to about 1: 1.

  The compounds and / or compositions of the present disclosure can be used to treat a variety of conditions in response to nitroxyl therapy. For example, the disclosed compounds and / or compositions can be used to treat or prevent the occurrence of cardiovascular disease. In certain embodiments, a nitroxyl donating composition of the present disclosure may be used to treat a cardiovascular disease, ischemia / reperfusion injury, pulmonary hypertension, or another condition that responds to nitroxyl therapy. it can. In certain embodiments, the nitroxyl donating compositions of the present disclosure can be used to treat heart failure. In certain embodiments, the compounds and / or compositions of the present disclosure can be used to treat decompensated heart failure (eg, acute decompensated heart failure). In certain embodiments, the compounds and / or compositions of the present disclosure can be used to treat systolic heart failure. In certain embodiments, the compounds and / or compositions of the present disclosure can be used to treat diastolic heart failure.

  In one aspect, compounds and / or compositions of the present disclosure can be administered by parenteral (eg, subcutaneous, intramuscular, intravenous or intradermal) administration. When administered parenterally (eg, intravenously) to human subjects, for example, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure can be about 5 μg / kg / min to about 100 μg / kg / min. The dose can be administered. In certain embodiments, an N-hydroxysulfonamide type nitroxyl donor useful in a pharmaceutical composition of the present disclosure is administered to a human subject in an amount of about 10 μg / kg / min to about 70 μg / kg / min. Can do. In certain embodiments, an N-hydroxysulfonamide type nitroxyl donor useful in a pharmaceutical composition of the present disclosure is administered to a human subject in an amount of about 15 μg / kg / min to about 50 μg / kg / min. Can do. In certain embodiments, an N-hydroxysulfonamide type nitroxyl donor useful in a pharmaceutical composition of the present disclosure is administered to a human subject in an amount of about 20 μg / kg / min to about 30 μg / kg / min. Can do. In certain embodiments, an N-hydroxysulfonamide type nitroxyl donor useful in a pharmaceutical composition of the present disclosure is administered to a human subject in an amount of about 10 μg / kg / min to about 20 μg / kg / min. Can do.

  In another embodiment, the compounds and / or compositions of the present disclosure can be formulated for oral administration. Compounds for oral administration can be formulated as liquid or solid dosage forms. In certain embodiments where the nitroxyl donor is formulated as an oral liquid dosage form, polyethylene glycol 300 (PEG 300) may serve as an exemplary additive.

Five compounds useful for CXL-1020 and pharmaceutical compositions of the present disclosure (of formulas (1), (2), (83), (84), and (85)) using a canine tachycardia pacing model of heart failure Figure 2 is a graph showing the hemodynamic profile of compound) (see Example 3). Each compound was administered intravenously in an amount of 100 μg / kg / min. Hemodynamic parameters were obtained 180 minutes after administration of each compound. Compounds useful for CXL-1020 and the pharmaceutical compositions of the present disclosure (Formulas (1), (2), (83), (84)) after 24 hours infusion at multiple doses using a canine peripheral vein toxicity model , (85) and (86))) (see Example 5). Key inflammatory markers measured include leukocytes (WBC), fibrinogen, and C-reactive protein (CRP). 72 hours central catheter using various doses of CXL-1020 and four compounds useful for pharmaceutical compositions of the present disclosure (compounds of formulas (1), (2), (83) and (84)) FIG. 5 shows inflammation measurements observed using an implanted dog model (see Example 5). The scores shown in the table are based on microscopic pathological findings of edema, hemorrhage, vascular inflammation and perivascular inflammation observed at and around the catheter tip and the proximal portion of the catheter tip. . Toxicological profile of CXL-1020 and two compounds of the present disclosure (compounds of formulas (2) and (86)) formulated at pH 4 or 6 after 24 hours infusion at an amount of 3 μg / kg / min It is a figure which shows evaluation.

  The present invention includes the following.

  (1.) A method of treating heart failure comprising administering a nitroxyl donor composition to a human patient, said composition being in human plasma at pH 7.4 according to the procedure described in Example 2 Comprising a N-hydroxysulfonamide type nitroxyl donor having a half-life of greater than 10 minutes as measured by and a cyclodextrin.

  (2.) The N-hydroxysulfonamide type nitroxyl donor has a half-life of about 12 minutes to about 85 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. The method according to (1.) above.

  (3) The N-hydroxysulfonamide type nitroxyl donor has a half-life of about 25 minutes to about 75 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. The method according to (1.) above.

  (4) The above (1), wherein the N-hydroxysulfonamide type nitroxyl donor has a half-life of less than 95 minutes when measured in human plasma at pH 7.4 under the conditions specified in Example 2. .).

  (5.) From the above (1.) to (4.), wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having 6 or 7 sulfo-n-butyl ether groups per cyclodextrin molecule. ).

  (6.) The method according to any one of (1) to (4) above, wherein the cyclodextrin is CAPTISOL (registered trademark).

  (7) The above (1), wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is about 0.02: 1 to about 2: 1. .) To (6.).

  (8.) The molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.05: 1 to about 1.5: 1. The method according to any one of (1.) to (6.).

  (9) The above (1), wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is about 0.5: 1 to about 1: 1. .) To (6.).

  (10.) The method according to any one of (1) to (9) above, wherein the composition is suitable for parenteral administration.

  (11.) The method according to (10) above, wherein the composition is suitable for intravenous administration.

  (12.) The method of (10.) or (11.) above, wherein the composition is formulated at a pH of about 4 to about 6.

  (13.) The method of (10) or (11) above, wherein the composition is formulated at a pH of about 5 to about 6.

  (14.) The method of (10.) or (11.) above, wherein the composition is formulated at a pH of about 5.5 to about 6.

  (15.) The method according to any one of (1.) to (14.) above, wherein the heart failure is acute decompensated heart failure.

  (16.) The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1)

である、上記（１．）から（１５．）のいずれか１つに記載の方法。

The method according to any one of (1.) to (15.) above.

  (17) The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (2)

である、上記（１．）から（１５．）のいずれか１つに記載の方法。

The method according to any one of (1.) to (15.) above.

  (18) A method for treating heart failure, wherein a human patient has an N-hydroxysulfonamide having a half-life of greater than 10 minutes as measured in human plasma at pH 7.4 by the procedure described in Example 2 Administering a nitroxyl donor composition comprising a type nitroxyl donor, wherein the composition is administered parenterally at a pH of about 5 to about 6.5.

  (19.) The method according to (18) above, wherein the composition is administered intravenously.

  (20.) The method of (18.) or (19.) above, wherein the composition is administered at a pH of about 5.5 to about 6.

  (21.) The method according to (18.) or (19.) above, wherein the composition is administered at a pH of about 6.

  (22.) The N-hydroxysulfonamide type nitroxyl donor has a half-life of about 12 minutes to about 85 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. The method according to any one of (18.) to (21.) above.

  (23.) The N-hydroxysulfonamide type nitroxyl donor has a half-life of about 25 minutes to about 75 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. The method according to any one of (18.) to (21.) above.

  (24.) The above (18) wherein said N-hydroxysulfonamide type nitroxyl donor has a half-life of less than 95 minutes when measured in human plasma at pH 7.4 under the conditions specified in Example 2. .) To (21.).

  (25.) The method according to any one of (18.) to (24.) above, wherein the composition further comprises a stabilizer.

  (26.) The method according to (25) above, wherein the stabilizer is cyclodextrin.

  (27.) The method according to (26) above, wherein the cyclodextrin is β-cyclodextrin.

  (28.) The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1)

である、上記（１８．）から（２７．）のいずれか１つに記載の方法。

The method according to any one of (18.) to (27.) above.

  (29.) The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (2)

である、上記（１８．）から（２７．）のいずれか１つに記載の方法。

The method according to any one of (18.) to (27.) above.

  (30.) comprising an N-hydroxysulfonamide type nitroxyl donor having a half-life of greater than 10 minutes as measured in human plasma at pH 7.4 by the procedure described in Example 2, and an aqueous buffer, A pharmaceutical composition having a pH of 5 to about 6.

  (31.) The pharmaceutical composition of (30.) above, wherein the aqueous buffer provides the composition with a pH of about 5.5 to about 6.2.

  (32.) The pharmaceutical composition according to (30.) above, wherein the aqueous buffer provides a pH of about 6 to the composition.

  (33.) The pharmaceutical composition according to any one of (30.) to (32.) above, wherein the buffer is a phosphate or acetate buffer.

  (34.) The pharmaceutical composition according to (33), wherein the buffer is a potassium phosphate buffer.

  (35.) The pharmaceutical composition according to (33) above, wherein the buffer solution is a potassium acetate buffer solution.

  (36.) The pharmaceutical composition according to any one of (30.) to (35.), further comprising a stabilizer.

  (37.) The pharmaceutical composition according to (36.) above, wherein the stabilizer is cyclodextrin.

  (38.) The pharmaceutical according to (37) above, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having 6 or 7 sulfo-n-butyl ether groups per cyclodextrin molecule. Composition.

  (39.) The pharmaceutical composition according to (37.) or (38.) above, wherein the cyclodextrin is CAPTISOL (registered trademark).

  (40.) The above (37), wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.02: 1 to about 2: 1. .) To (39.) The pharmaceutical composition according to any one of (39).

  (41.) The molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.05: 1 to about 1.5: 1. (37.) The pharmaceutical composition according to any one of (39.).

  (42.) The above (37), wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.5: 1 to about 1: 1. .) To (39.) The pharmaceutical composition according to any one of (39).

  (43.) The N-hydroxysulfonamide type nitroxyl donor has a half-life of about 12 minutes to about 85 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. The pharmaceutical composition according to any one of (30.) to (42.) above.

  (44.) The N-hydroxysulfonamide type nitroxyl donor has a half-life of about 25 minutes to about 75 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. The pharmaceutical composition according to any one of (30.) to (42.) above.

  (45.) The N-hydroxysulfonamide-type nitroxyl donor has a half-life of less than 95 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2 (30 .) To (42.) The pharmaceutical composition according to any one of (42).

  (46.) The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1)

である、上記（３０．）から（４２．）のいずれか１つに記載の医薬組成物。

The pharmaceutical composition according to any one of (30.) to (42.) above.

  (47.) The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (2)

である、上記（３０．）から（４２．）のいずれか１つに記載の医薬組成物。

The pharmaceutical composition according to any one of (30.) to (42.) above.

  (48.) (i) an N-hydroxysulfonamide type nitroxyl donor having a half-life of greater than 10 minutes as measured in human plasma at pH 7.4 by the procedure described in Example 2, and (ii) cyclo A pharmaceutical composition comprising dextrin.

  (49.) The N-hydroxysulfonamide type nitroxyl donor has a half-life of about 12 minutes to about 85 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. The pharmaceutical composition according to (48) above.

  (50.) The N-hydroxysulfonamide type nitroxyl donor has a half-life of about 25 minutes to about 75 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. The pharmaceutical composition according to (48) above.

  (51.) The above (48) wherein said N-hydroxysulfonamide type nitroxyl donor has a half-life of less than 95 minutes when measured in human plasma at pH 7.4 under the conditions specified in Example 2. .).

  (52.) From (48.) to (51.) above, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having 6 or 7 sulfo-n-butyl ether groups per cyclodextrin molecule. ) The pharmaceutical composition according to any one of

  (53.) The pharmaceutical composition according to any one of (48.) to (51.), wherein the cyclodextrin is CAPTISOL (registered trademark).

  (54.) The above (48), wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.02: 1 to about 2: 1. .) To (53.) The pharmaceutical composition according to any one of (53).

  (55.) The molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.05: 1 to about 1.5: 1. (48.) The pharmaceutical composition according to any one of (53.).

  (56.) The above (48), wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.5: 1 to about 1: 1. .) To (53.) The pharmaceutical composition according to any one of (53).

  (57.) The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1)

である、上記（４８．）から（５３．）のいずれか１つに記載の医薬組成物。

The pharmaceutical composition according to any one of (48.) to (53.) above.

  (58.) The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (2)

である、上記（４８．）から（５３．）のいずれか１つに記載の医薬組成物。

The pharmaceutical composition according to any one of (48.) to (53.) above.

  (59.) A composition comprising an N-hydroxysulfonamide type nitroxyl donor having a half-life of greater than 10 minutes as measured in human plasma at pH 7.4 by the procedure described in Example 2 and a cyclodextrin A mixture wherein the molar ratio between said N-hydroxysulfonamide type nitroxyl donor present in said cyclodextrin is from about 0.02: 1 to about 2: 1.

  (60.) The mixture according to (59.), which is formed by lyophilization.

  (61.) The molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.05: 1 to about 1.5: 1. (59.) or a mixture according to (60.) above.

  (62.) The above (61), wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.5: 1 to about 1: 1. .).

  (63.) The mixture according to any one of (59.) to (62.), further comprising a buffering agent.

  (64.) The mixture according to (63.), wherein the buffer is potassium acetate.

  (65.) The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1)

である、上記（５９．）から（６４．）のいずれか１つに記載の混合物。

The mixture according to any one of (59.) to (64.) above.

  (66.) The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (2)

である、上記（５９．）から（６４．）のいずれか１つに記載の混合物。

The mixture according to any one of (59.) to (64.) above.

  (67.) Use of the pharmaceutical composition according to any one of (30.) to (58.) above for the manufacture of a medicament useful for treating a cardiovascular disease.

  (68.) Use of the pharmaceutical composition according to any one of (30.) to (58.) above for the manufacture of a medicament useful for treating heart failure.

  (69.) Use of the pharmaceutical composition according to any one of (30.) to (58.) above for the manufacture of a medicament useful for treating acute decompensated heart failure.

  (70.) The pharmaceutical composition according to any one of (30.) to (58.) above, for use in the treatment of a cardiovascular disease.

  (71.) The pharmaceutical composition according to any one of (30.) to (58.) above, for use in the treatment of heart failure.

  (72.) The pharmaceutical composition according to any one of (30.) to (58.) above, for use in the treatment of acute decompensated heart failure.

4.1. Definitions Unless otherwise stated explicitly, the following terms used herein have the meanings set forth below.

  “Pharmaceutically acceptable salt” refers to a salt of any of the therapeutic agents disclosed herein, which salt is any of a variety of organic and inorganic counterions known in the art. And the salts are pharmaceutically acceptable. When the therapeutic agent contains an acidic functional group, various exemplary embodiments of the counterion are sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like. Where the therapeutic agent contains a basic functional group, pharmaceutically acceptable salts include, for example, organic or inorganic acids such as hydrochloric acid, hydrobromic acid, tartaric acid, mesylic acid, acetic acid, maleic acid, and oxalic acid. , As a counter ion. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acidic phosphate, lactate, salicylic acid Salt, acid citrate, tartrate, oleate, tannate, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, besylate, fumarate, gluconate, Included are glucaronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate. Thus, a salt can be prepared from a compound of any one of the formulas disclosed herein having an acidic functional group such as a carboxylic acid functional group and a pharmaceutically acceptable inorganic or organic base. . Suitable bases include, but are not limited to, alkali metal hydroxides such as sodium, potassium and lithium, alkaline earth metal hydroxides such as calcium and magnesium, hydroxides of other metals such as aluminum and zinc Ammonia, and organic amines such as mono-, di- or trialkylamines which are unsubstituted or hydroxy-substituted, dicyclohexylamine, tributylamine, pyridine, N-methyl-N-ethylamine, diethylamine, triethylamine, mono-, bis- or Mono-, bis- or tris- (2-hydroxy-lower-alkylamine) such as tris- (2-hydroxyethyl) amine, 2-hydroxy-tert-butylamine, or tris- (hydroxymethyl) methylamine, N, N- N, N-di-lower-alkyl-N- (hydroxy-lower-alkyl) -amine, such as methyl-N- (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, N-methyl-D -Glucamine and amino acids such as arginine and lysine are included. Salts can also be prepared from a compound of any one of the formulas disclosed herein having a basic functional group such as an amino functional group and a pharmaceutically acceptable inorganic or organic acid. Suitable acids include hydrogen sulfide, citric acid, acetic acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, phosphoric acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, succinic acid Maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

“Pharmaceutically acceptable additives” are used as carriers, excipients, adjuvants, binders, and / or vehicles to deliver therapeutic agents to a patient, or their handling properties or storage. Any substance that is not itself a therapeutic agent that is added to a pharmaceutical composition to improve properties, or that allows or facilitates the formation of a compound or pharmaceutical composition into a unit dosage form for administration Point to. Pharmaceutically acceptable excipients are well known in the pharmaceutical art, for example, Gennaro, Ed, Remington:. . The Science and Practice of Pharmacy, 20 th Ed (Lippincott Williams & Wilkins, Baltimore, MD, 2000) and Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, DC (eg, 1st, 2nd and 3rd editions, 1986, 1994 and 2000, respectively). As known to those skilled in the art, pharmaceutically acceptable additives can provide various functions, such as wetting agents, buffering agents, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, Can be described as preservatives, surfactants, colorants, flavoring agents, and sweetening agents. Examples of pharmaceutically acceptable additives include, but are not limited to, (1) sugars such as lactose, glucose and sucrose, (2) starches such as corn starch and potato starch, (3) sodium carboxymethylcellulose, ethylcellulose Cellulose and its derivatives such as cellulose acetate, hydroxypropylmethylcellulose, and hydroxypropylcellulose, (4) powdered tragacanth, (5) malt, (6) gelatin, (7) talc, (8) cocoa butter and suppository waxes (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, (10) glycols such as propylene glycol, (11) glycerin, sorbitol, mannitol and poly Polyols such as tylene glycol, (12) esters such as ethyl oleate and ethyl laurate, (13) agar, (14) buffering agents such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) exotherm. Substance-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) pH buffered solution, (21) polyester, polycarbonate and / or polyanhydride, and (22) Other non-toxic compatible substances used in pharmaceutical formulations are included.

  “Unit dosage form” refers to a physically discrete unit suitable as a unit dosage for humans or animals. Each unit dosage form can contain a predetermined quantity of the therapeutic agent calculated to produce the desired effect.

  Unless otherwise indicated, “patient” refers to an animal, such as a mammal, including but not limited to a human. Thus, the methods disclosed herein can be useful for human therapy and veterinary applications. In certain embodiments, the patient is a mammal. In certain embodiments, the patient is a human.

  An “effective amount” is a combination of a therapeutic agent or a pharmaceutically acceptable salt thereof that is to be effective in a given therapeutic form, in combination with its efficacy parameters and potential toxicity, and based on the knowledge of a practitioner. Refers to these quantities. As is understood in the art, an effective amount can be administered in one or more doses.

  “Treatment”, “treating”, and the like are techniques for obtaining beneficial or desired results, including clinical results. For the purposes of this disclosure, beneficial or desired results include, but are not limited to, the onset and / or suppression of the occurrence and / or suppression of a condition, or the number and / or number of symptoms associated with the condition. To reduce the severity of these conditions, such as reducing the severity, improve the quality of life of people suffering from the condition, reduce the dose of other medications needed to treat the condition, Enhancing the effect of another medication that the patient is taking and / or extending the survival of the patient with the condition.

  “Prevent”, “prevention” and the like refer to reducing the likelihood of a condition occurring in a patient who does not have a condition but is at risk of developing it. A “at risk” patient may or may not have a detectable condition and has exhibited a detectable condition prior to the treatment methods disclosed herein. May or may not have been shown. “At risk” means that a patient has one or more so-called risk factors that are correlated with the occurrence of a condition and are measurable parameters known in the art. Patients with one or more of these risk factors are more likely to develop the condition than patients without these risk factors.

  “Positive inotrope” refers to an agent that causes an improvement in myocardial contractile function. Exemplary positive inflators are beta-adrenergic receptor agonists, inhibitors of phosphodiesterase activity, and calcium sensitizers. Beta-adrenergic receptor agonists include dopamine, dobutamine, terbutaline, and isoproterenol, among others. Analogs and derivatives of such compounds are also contemplated. For example, US Pat. No. 4,663,351 discloses dobutamine prodrugs that can be administered orally.

  A condition “responsive to nitroxyl therapy” is any condition in which, under physiological conditions, administration of a compound that provides an effective amount of nitroxyl treats and / or prevents a condition whose terms are defined herein. States are included. A condition whose symptoms are suppressed or alleviated upon administration of a nitroxyl donor is a condition in response to nitroxyl therapy.

  “Pulmonary hypertension” or “PH” refers to a condition in which pulmonary artery pressure increases. The current hemodynamic definition of PH is mean pulmonary artery blood pressure (MPAP) at rest above 25 mgHg. Badesch et al., J. Amer. Coll. Cardiol. 54 (Suppl.): S55-S66 (2009).

  “N / A” means not evaluated.

“(C ₁ -C ₆ ) alkyl” refers to linear and branched saturated hydrocarbon structures having 1, 2, 3, 4, 5, or 6 carbon atoms. When an alkyl residue having a particular carbon number is named, all geometric isomers having that carbon number are intended to be included. Thus, for example, “propyl” includes n-propyl and iso-propyl, and “butyl” includes n-butyl, sec-butyl, iso-butyl and tert-butyl. Examples of (C ₁ -C ₆ ) alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-hexyl and the like.

“(C ₁ -C ₄ ) alkyl” refers to linear and branched saturated hydrocarbon structures having 1, 2, 3 or 4 carbon atoms. Examples of (C ₁ -C ₄ ) alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, and tert-butyl.

“(C ₃ -C ₅ ) alkyl” refers to linear and branched saturated hydrocarbon structures having 3, 4 or 5 carbon atoms. When an alkyl residue having a particular carbon number is named, all geometric isomers having that carbon number are intended to be included. Thus, for example, “propyl” includes n-propyl and iso-propyl, and “butyl” includes n-butyl, sec-butyl, iso-butyl, and tert-butyl. Examples of (C ₃ -C ₅ ) alkyl groups include n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl and the like.

“(C ₂ -C ₄ ) alkenyl” refers to a straight or branched unsaturated hydrocarbon group having 2, 3, or 4 carbon atoms and a double bond at any position, for example, ethenyl 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methylethenyl, 1-methyl-1-propenyl, 2-methyl-2-propenyl, 2-methyl-1- It refers to propenyl, 1-methyl-2-propenyl and the like.

“(C ₂ -C ₃ ) alkynyl” refers to a straight chain acyclic hydrocarbon having 2 or 3 carbon atoms and containing at least one carbon-carbon double bond. Examples of (C ₂ -C ₃ ) alkenyl include -vinyl, -allyl and 1-prop-1-enyl.

“(C ₅ -C ₇ ) heterocycloalkyl” means a 5-, 6-, or 7-membered saturated or unsaturated, bridge containing 1, 2, 3 or 4 ring heteroatoms , Monocyclic or bicyclic heterocycles, wherein each ring heteroatom is independently selected from nitrogen, oxygen and sulfur. Examples of (C ₅ -C ₇ ) heterocycloalkyl groups include pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydro-oxazinyl, tetrahydrofuran, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine , Pyridazine, pyrimidine, pyrazine, tetrahydrofuranone, γ-butyrolactone, α-pyran, γ-pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepane, oxazine, tetrahydro-oxazinyl , Isothiazole, pyrazolidine and the like.

  “(5- or 6-membered) heteroaryl” refers to a 5- or 6-membered monocyclic aromatic heterocycle, ie, a monocyclic aromatic ring contains at least one ring heteroatom, such as Contains 1, 2, 3 or 4 ring heteroatoms, each of the ring heteroatoms being independently selected from nitrogen, oxygen and sulfur. Examples of (5- or 6-membered) heteroaryl include pyridyl, pyrrolyl, furyl, imidazolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2 , 5-oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3 , 5-triazinyl, and thiophenyl.

  “Halo” refers to —F, —Cl, —Br or —I.

The term “sulfo-n-butyl ether derivative of β-cyclodextrin” means that the hydrogen atom is — (CH ₂ ) ₄ —S (O) ₂ —OH or — (CH ₂ ) ₄ —S (O) ₂ —O. ^- is replaced by Z ^+, respectively _{-O- (CH 2) 4 -S (} O) 2 -OH or _{-O- (CH 2) 4 -S (} O) 2 -O - by giving ^{Z +} groups Refers to β-cyclodextrin having at least one —OH group to be derivatized, where Z ⁺ is a cation such as sodium, potassium, ammonium, tetramethylammonium and the like. In one embodiment, each Z is sodium.

4.2 N-hydroxysulfonamide-type nitroxyl donors Under physiological conditions, N-hydroxysulfonamide-type nitroxyl donors that have a sufficiently long half-life are N-hydroxysulfonamide-type nitroxyl donors that have a shorter half-life It has been discovered that it has a significantly better toxicological profile compared to the body (eg CXL-1020). These longer half-life nitroxyl donors achieve a potency level similar to CXL-1020 when administered intravenously, but show significant reduction in side effects (eg, irritation and / or inflammation) (Examples) See 4-6). In addition, these nitroxyl donors provide clinically desirable onset of hemodynamic effects within 1 hour.

  Without being bound by theory, the half-life is substantially less than 10 minutes when measured in PBS or human plasma (see Example 2) by experiments reported in the examples of the present disclosure. It is suggested that nitroxyl donors such as CXL-1020 produce high local concentrations of nitroxyl upon administration and that the high local concentration of nitroxyl is responsible for the observed side effects. At high concentrations, nitroxyl dimerizes to form hyponitrous acid, which can generate hydroxyl radicals. Alternatively or additionally, the peroxide released from the leukocytes can react with nitroxyl to form hydroxyl radicals. Hydroxyl radicals are toxic to endothelial cells and can lead to inflammation or intolerance. Nitroxyl compounds with longer half-life can theoretically generate hydroxyl radicals by a similar mechanism, but the formation of such radicals is expected to decrease due to the low concentration of nitroxyl. Thus, the ability of nitroxyl to dimerize or react with peroxide is reduced. Thus, compounds with a very long half-life (eg, greater than 95 minutes as measured in human plasma according to the method described in Example 2) are expected to have an advantageous toxicological profile. The However, these compounds are expected to be less potent because they appear to be cleared from the circulation and / or diluted prior to the formation of substantial nitroxyl.

  Accordingly, the present disclosure follows the procedure described in Example 2, respectively, in an aerated phosphate buffered saline (PBS) solution at pH 7.4, or in an anticoagulant (eg, heparin or sodium citrate). Provided is a pharmaceutical composition comprising an N-hydroxysulfonamide type nitroxyl donor having a half-life greater than about 10 minutes as measured in human plasma at pH 7.4 in the presence. In certain embodiments, the present disclosure follows the procedure described in Example 2, respectively, in a pH 7.4 aerated phosphate buffered saline (PBS) solution, or an anticoagulant (eg, heparin or quencher). There is provided a pharmaceutical composition comprising an N-hydroxysulfonamide type nitroxyl donor having a half-life greater than about 17 minutes as measured in human plasma at pH 7.4 in the presence of sodium acid.

  Each in accordance with the procedure described in Example 2, in pH 7.4 aerated phosphate buffered saline (PBS) solution, or in the presence of an anticoagulant (eg, heparin or sodium citrate), pH 7.4. N-hydroxysulfonamide type nitroxyl donors, which have a half-life in the range of about 12 minutes to about 85 minutes as measured in human plasma, have advantageous potency and It has been found to have an improved toxicological profile. In certain embodiments, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure are each aerated phosphate buffered saline at pH 7.4 according to the procedure described in Example 2. It has a half-life of about 15 minutes to about 80 minutes as measured in human plasma at pH 7.4 in water (PBS) solution or in the presence of an anticoagulant (eg, heparin or sodium citrate). In certain embodiments, nitroxyl donors useful in the pharmaceutical compositions of this disclosure are each in a pH 7.4 aerated phosphate buffered saline (PBS) solution according to the procedure described in Example 2. Or has a half-life of about 25 minutes to about 75 minutes as measured in human plasma at pH 7.4 in the presence of an anticoagulant (eg, heparin or sodium citrate). In certain embodiments, nitroxyl donors useful in the pharmaceutical compositions of this disclosure are each in a pH 7.4 aerated phosphate buffered saline (PBS) solution according to the procedure described in Example 2. Or has a half-life of about 25 minutes to about 60 minutes as measured in human plasma at pH 7.4 in the presence of an anticoagulant (eg, heparin or sodium citrate). In certain embodiments, nitroxyl donors useful in the pharmaceutical compositions of this disclosure are each a pH 7.4 aerated phosphate buffered saline (PBS) solution, according to the procedure described in Example 2, or It has a half-life of about 35 minutes to about 60 minutes as measured in human plasma at pH 7.4 in the presence of an anticoagulant (eg, heparin or sodium citrate). In certain embodiments, nitroxyl donors useful in the pharmaceutical compositions of this disclosure are each in a pH 7.4 aerated phosphate buffered saline (PBS) solution according to the procedure described in Example 2. Alternatively, it has a half-life of about 35 minutes to about 50 minutes as measured in human plasma at pH 7.4 in the presence of an anticoagulant (eg, heparin or sodium citrate). In certain embodiments, nitroxyl donors useful in the pharmaceutical compositions of this disclosure are each a pH 7.4 aerated phosphate buffered saline (PBS) solution, according to the procedure described in Example 2, or Has a half-life of about 40 minutes to about 50 minutes in human plasma at pH 7.4 in the presence of an anticoagulant (eg, heparin or sodium citrate).

  N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure have a physiological pH (ie, a pH of about 7.4) and a physiological temperature (ie, a temperature of about 37 ° C.) ( In physiological conditions ") nitroxyl can be donated. The level of nitroxyl donating ability can be expressed as a percentage of the maximum theoretical stoichiometric amount of the nitroxyl donor of the N-hydroxysulfonamide type. A compound that provides a “significant nitroxyl level” refers, in various embodiments, to about 40% or more, about 50% or more, about 60% or more, about 70% of the theoretical maximum amount of nitroxyl under physiological conditions. This means an N-hydroxysulfonamide type nitroxyl donor useful for the pharmaceutical composition of the present disclosure that provides about 80% or more, about 90% or more, or about 95% or more. In certain embodiments, N-hydroxysulfonamide type nitroxyl donors useful in pharmaceutical compositions donate about 70% to about 90% of the theoretical maximum amount of nitroxyl. In certain embodiments, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure donate about 85% to about 95% of the theoretical maximum amount of nitroxyl. In certain embodiments, N-hydroxysulfonamide type nitroxyl donors useful in pharmaceutical compositions donate about 90% to about 95% of the theoretical maximum amount of nitroxyl. Compounds that donate less than about 40% or less than about 50% of the theoretical maximum amount of nitroxyl are still nitroxyl donors and can be used in the disclosed methods. N-hydroxysulfonamide type nitroxyl donors that donate less than about 50% of the theoretical amount of nitroxyl can be used in the disclosed methods, but N-hydroxysulfones that donate higher levels of nitroxyl. Higher dosage levels may be required compared to amide nitroxyl donors.

  It is understood that N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure can also provide a limited amount of nitric oxide as long as the nitroxyl donation exceeds the nitric oxide donation. Like. In certain embodiments, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure can donate about 25 mol% or less nitric oxide under physiological conditions. In certain embodiments, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure can donate about 20 mol% or less nitric oxide under physiological conditions. In certain embodiments, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of the present disclosure can donate about 15 mol% or less nitric oxide under physiological conditions. In certain embodiments, the donor compound that is an N-hydroxysulfonamide-type nitroxyl donor useful in the pharmaceutical compositions of the present disclosure provides no more than about 10 mol% nitric oxide under physiological conditions. Can do. In certain embodiments, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure can donate about 5 mol% or less nitric oxide under physiological conditions. In certain embodiments, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of the present disclosure can donate about 2 mol% or less nitric oxide under physiological conditions. In certain embodiments, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure donate small amounts (eg, about 1 mol% or less) of nitric oxide under physiological conditions. can do.

  Specific embodiments of N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure are presented in Tables 1 and 2. The compounds listed in Table 1 were developed to optimize the half-life and toxicological profile of the nitroxyl donor according to one of the objectives of this disclosure. The compounds listed in Table 2 have already been described (see, eg, US Pat. No. 8,030,356, the entire contents of which are incorporated herein by reference). The compounds listed in Tables 1 and 2 are generally measured in aerated phosphate buffered saline (PBS) solution and / or in plasma (see Table 4 in Section 5.2). ) Have a half-life of more than 10 minutes.

  In certain embodiments, the nitroxyl donors listed in Table 1 and Table 2 can be converted to their pharmaceutically acceptable salts. Exemplary salts include, but are not limited to, oxalate, chloride, bromide, iodide, sulfate, citrate, acetate, trifluoroacetate, nitrate, bisulfate, phosphate, Acid phosphate, isonicotinate, lactate, glutamate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, hydrogen tartrate, ascorbate, succinate , Maleate, gentianate, fumarate, gluconate, glucoronate, saccharinate, formate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- Toluene sulfonate and pamoate are included.

  In some embodiments, the N-hydroxyl group of the compounds listed in Tables 1 and 2 is esterified to produce a compound of general formula (99), shown below:

（式中、

(Where

は、表１および２に図示されている化合物の芳香族、複素芳香族または多環式部分を表し（存在する場合、表１および２に図示されている置換基を含む）、Ｒは、水素、−（Ｃ_１〜Ｃ_６）アルキル、−（Ｃ_２〜Ｃ_４）アルケニル、フェニル、ベンジル、シクロペンチル、シクロヘキシル、−（Ｃ_５〜Ｃ_７）ヘテロシクロアルキル、ベンジルオキシ、−Ｏ−（Ｃ_１〜Ｃ_６）アルキル、−ＮＨ_２、−ＮＨ−（Ｃ_１〜Ｃ_４）アルキル、または−Ｎ（（Ｃ_１〜Ｃ_４）アルキル）_２であり、前記−（Ｃ_１〜Ｃ_６）アルキル、−（Ｃ_２〜Ｃ_４）アルケニル、フェニル、ベンジル、シクロペンチル、シクロヘキシル、−（Ｃ_５〜Ｃ_７）ヘテロシクロアルキル、ベンジルオキシ、−Ｏ−（Ｃ_１〜Ｃ_６）アルキル、−ＮＨ−（Ｃ_１〜Ｃ_４）アルキルまたは−Ｎ（（Ｃ_１〜Ｃ_４）アルキル）_２は、無置換とすることができるか、またはハロ、−（Ｃ_１〜Ｃ_６）アルキル、−（Ｃ_２〜Ｃ_４）アルケニル、−（Ｃ_２〜Ｃ_３）アルキニル、−（５員または６員の）ヘテロアリール、−Ｏ−（Ｃ_１〜Ｃ_６）アルキル、−Ｓ−（Ｃ_１〜Ｃ_６）アルキル、−Ｃ（ハロ）_３、−ＣＨ（ハロ）_２、−ＣＨ_２（ハロ）、−ＣＮ、−ＮＯ_２、−ＮＨ_２、−ＮＨ−（Ｃ_１〜Ｃ_４）アルキル、−Ｎ（−（Ｃ_１〜Ｃ_４）アルキル）_２、−Ｃ（＝Ｏ）（Ｃ_１〜Ｃ_４）アルキル、−Ｃ（＝Ｏ）Ｏ（Ｃ_１〜Ｃ_４）アルキル、−ＯＣ（＝Ｏ）（Ｃ_１〜Ｃ_４）アルキル、−ＯＣ（＝Ｏ）ＮＨ_２、−Ｓ（＝Ｏ）（Ｃ_１〜Ｃ_４）アルキル、もしくは−Ｓ（＝Ｏ）_２（Ｃ_１〜Ｃ_４）アルキルから選択される１つまたは複数の置換基により置換され得る）を生成することができる。特定の実施形態では、Ｒは、メチル、エチル、ベンジルまたはフェニルである。特定の実施形態では、Ｒは、メチルまたはエチルである。特定の実施形態では、Ｒはメチルである。特定の実施形態では、Ｒはエチルである。特定の実施形態では、Ｒは、ベンジルまたはフェニルである。特定の実施形態では、Ｒはベンジルである。特定の実施形態では、Ｒはフェニルである。

Represents an aromatic, heteroaromatic or polycyclic moiety of the compounds illustrated in Tables 1 and 2 (including the substituents illustrated in Tables 1 and 2, if present), and R is hydrogen , - _(C 1 ~C ₆₎ alkyl, - _(C 2 ~C ₄₎ alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, - _(C 5 ~C ₇₎ heterocycloalkyl, benzyloxy, -O- _{(C 1} -C _{6) alkyl, -NH 2, -NH- (C 1} ~C 4) alkyl or _{-N, ((C 1 ~C 4} ) _{alkyl) 2,} wherein - _(C 1 ~C ₆₎ alkyl, - _(C 2 ~C ₄₎ alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, - _(C 5 ~C ₇₎ heterocycloalkyl, benzyloxy, -O- _(C 1 _{~C 6)} alkyl, -NH- (C -C ₄₎ alkyl or -N _((C 1 ~C _{4) alkyl) 2,} or may be unsubstituted, or halo, - _(C 1 ~C ₆₎ alkyl, - _(C 2 -C ₄ ) alkenyl, - _(C 2 -C ₃₎ alkynyl, - (5- or 6-membered) heteroaryl, -O- _(C 1 -C ₆₎ alkyl, -S- _(C 1 -C ₆₎ alkyl, - C (halo) ₃ , —CH (halo) ₂ , —CH ₂ (halo), —CN, —NO ₂ , —NH ₂ , —NH— (C ₁ -C ₄ ) alkyl, —N (— (C ₁ -C _{4) alkyl) 2, -C (= O)} (C 1 ~C 4) _{alkyl, -C (= O) O (} C 1 ~C 4) _{alkyl, -OC (= O) (C} 1 ~C _{4) alkyl, -OC (= O) NH 2} , -S (= O) (C 1 ~C 4) alkyl or -S (= _O) 2, ( ₁ -C ₄₎ may be substituted by one or more substituents selected from alkyl) can be generated. In certain embodiments, R is methyl, ethyl, benzyl or phenyl. In certain embodiments, R is methyl or ethyl. In certain embodiments, R is methyl. In certain embodiments, R is ethyl. In certain embodiments, R is benzyl or phenyl. In certain embodiments, R is benzyl. In certain embodiments, R is phenyl.

4.3 Determination of nitroxyl donating ability Compounds are readily tested for nitroxyl donation by routine experimentation. Since direct measurement of whether nitroxyl is donated is usually impractical, several analytical techniques are available as appropriate proxies to determine whether a compound donates nitroxyl. Accepted. For example, the compound of interest can be placed in a sealed container, in a solution, such as in phosphate buffered saline (PBS) or a phosphate buffer solution having a pH of about 7.4. After a sufficient time for dissociation such as several minutes to several hours has passed, the headspace gas is extracted and analyzed by gas chromatography and / or mass spectrometry to determine its composition. When N ₂ O gas is formed (which occurs by HNO dimerization), the test is positive for nitroxyl donation and the compound is considered a nitroxyl donor.

  For compounds in which the N-hydroxyl group of the N-hydroxysulfonamide type nitroxyl donor is esterified, porcine liver esterase (PLE) can be added to the stock solution used to perform headspace analysis.

If desired, nitroxyl donation can also be detected by exposing the test compound to metmyoglobin (Mb ³⁺ ). See Bazylinski et al., J. Amer. Chem. Soc. 107 (26): 7982-7986 (1985). Nitroxyl reacts with Mb ³⁺ to form an Mb ²⁺ -NO complex, which can be detected by changes in the UV / visible spectrum or by electron paramagnetic resonance (EPR). The Mb ²⁺ -NO complex has an EPR signal centered around a g value of about 2. On the other hand, nitric oxide reacts with ^{Mb 3+,} to form a ^Mb 3+ -NO complex, the complex, if any, has a very small EPR signal. Thus, if a compound reacts with Mb ³⁺ to form a complex detectable by common methods such as UV / visible light or EPR, this test is positive for nitroxyl donation.

4.4 Pharmaceutical Composition The present disclosure encompasses a pharmaceutical composition comprising a nitroxyl donor and at least one pharmaceutically acceptable additive. Examples of pharmaceutically acceptable additives include carriers, surfactants, thickeners or emulsifiers, solid binders, dispersion or suspension aids, solubilizers, colorants, flavoring agents, coating agents, These include such as disintegrants, lubricants, sweeteners, preservatives, isotonic agents, and any combinations thereof. The selection and use of pharmaceutically acceptable additives is taught, for example, in Troy, Ed., Remington: The Science and Practice of Pharmacy, 21 ^st Ed. (Lippincott Williams & Wilkins, Baltimore, MD, 2005). Yes.

  The pharmaceutical composition comprises the following: (1) for example drench (for example aqueous or non-aqueous solutions or suspensions), tablets (for example for buccal, sublingual and systemic absorption), caplets , Bolus, powder, granule, paste for tongue application, hard gelatin capsule, soft gelatin capsule, oral spray, troche, lozenge, pellet, syrup, suspension, elixir For oral administration as solutions, emulsions and microemulsions, or (2) for parenteral administration eg as a sterile solution or suspension, eg by subcutaneous, intramuscular, intravenous or epidural injection Can be formulated for administration in solid or liquid form, including those adapted to. The pharmaceutical composition can be for immediate release, sustained release or controlled release.

  The compounds and pharmaceutical compositions disclosed herein are capsules, sachets, tablets, powders, granules, solutions, suspensions in aqueous liquids, suspensions in non-aqueous liquids, oil-in-water types It can be prepared as any suitable unit dosage form such as a liquid emulsion, a water-in-oil liquid emulsion, a liposome or a bolus.

4.4.1 Compositions for Parenteral Administration The present disclosure provides nitroxyl donating compositions for parenteral (eg, intravenous) administration. In one embodiment, the pharmaceutical composition is formulated for intravenous administration by continuous infusion.

  Various embodiments of pharmaceutical compositions suitable for parenteral administration include, but are not limited to, either aqueous or non-aqueous sterile solutions (eg, antioxidants, buffers, statics, respectively). Fungi, and solutes that impart isotonicity to the intended recipient's blood to the formulation), and aqueous and non-aqueous sterile suspensions (eg, suspending agents, respectively) And a thickener). The formulation can be provided in unit-dose or multi-dose containers, such as sealed ampoules or vials, stored in a freeze-dried state that requires only the addition of a sterile liquid carrier such as water just prior to use. be able to. Alternatively, the formulation can be in liquid form.

  Pharmaceutical compositions administered parenterally can be administered in acidic, neutral or basic solutions. In one embodiment, the pharmaceutical composition comprising a nitroxyl donor has a pH of about 4 to about 5, such as a pH of about 4, about 4.5, about 4.8 or about 5 (including values therebetween). It can be formulated in an acidic solution. A pH of about 4 is generally considered optimal for formulating N-hydroxysulfonamide type nitroxyl donors in order to achieve reasonable donor stability, but formulation under such acidic conditions Has been found to potentially cause or exacerbate venous irritation after parenteral administration. The amount of irritation can be reduced by formulating the N-hydroxysulfonamide type nitroxyl donor in a less acidic medium (see Example 6 and FIG. 4).

  Accordingly, in certain embodiments, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure have a pH of about 5 to about 6.5, in some embodiments, in some embodiments. From about 5 to about 6, in some embodiments from about 5.5 to about 6, in some embodiments from about 5 to about 5.5, and in some embodiments from about 5.2 to about 6.2. About 5.5 to about 6.2 in some embodiments, about 5.8 to about 6.2 in some embodiments, and in certain embodiments about pH 6, for parenteral injection To be formulated. In another embodiment, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of the present disclosure is formulated for parenteral injection at a pH of about 5.

  To achieve the desired pH of the pharmaceutical composition, the N-hydroxysulfonamide type nitroxyl donor can be formulated in an aqueous buffer. For example, N-hydroxysulfonamide type nitroxyl donors can be formulated in phosphate or acetate buffer. In certain embodiments, the N-hydroxysulfonamide type nitroxyl donor is formulated in potassium phosphate or sodium phosphate buffer. In other embodiments, the N-hydroxysulfonamide type nitroxyl donor is formulated in potassium phosphate buffer or sodium phosphate buffer. In other embodiments, the N-hydroxysulfonamide type nitroxyl donor is formulated in potassium citrate buffer or sodium citrate buffer.

  Aqueous buffers can also contain suitable sugars to maintain a moderate osmolarity. For example, the pharmaceutical composition can include an appropriate amount of dextrose. The pharmaceutical composition illustrated in the examples of the present disclosure is a concentrate comprising an N-hydroxysulfonamide type nitroxyl donor, optionally a cyclodextrin (see section 4.4.3), and a suitable buffer. The product was generally prepared by diluting the product into an aqueous solution containing 5% dextrose (D5W) or 2.5% dextrose (D2.5W).

4.4.2 Compositions for oral administration A pharmaceutical composition comprising an N-hydroxysulfonamide type nitroxyl donor can be formulated for oral administration. Compounds for oral administration can be formulated as liquid or solid dosage forms. In certain embodiments where the nitroxyl donor is formulated as an oral liquid dosage form, polyethylene glycol 300 (PEG 300) may serve as an additive.

  Tablets for oral administration can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be mixed in suitable machines, optionally mixed with binders, lubricants, inert excipients, preservatives, surfactants or dispersants, in a free flowing form such as a powder or granules. It can be prepared by compressing the agent (s). Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid excipient. The tablets can optionally be coated or scored and can be formulated to provide delayed or controlled release of the active ingredient therein. Methods for formulating such delayed or controlled release compositions of pharmaceutically active ingredients, such as therapeutic agents herein and other compounds known in the art, are known and issued in the art. Some of them are disclosed in U.S. Patents, including but not limited to U.S. Pat. Nos. 4,369,174, 4,842,866, and references cited therein. Coating agents can be used to deliver compounds to the intestine (eg, US Pat. Nos. 6,638,534, 5,217,720, 6,569,457, and therein) (See cited references). One skilled in the art will recognize that in addition to tablets, other dosage forms can be formulated to provide delayed or controlled release of the active ingredient. Such dosage forms include, but are not limited to, capsules, granulating agents, and gel-cap agents.

4.4.3 Stabilization and Solubility Enhancing Agents It has been discovered that N-hydroxysulfonamide type nitroxyl donors can have stability problems when formulated for parenteral and oral administration. In particular, N-hydroxysulfonamide type nitroxyl donors gradually release nitroxyl and at least one by-product in the pharmaceutical composition, which can compromise the efficacy and safety of the composition. . For example, compounds of formula (1) and formula (2) release nitroxyl and sulfinic acid byproducts (compounds of formula (100) and formula (101), respectively) according to the following scheme.

  Furthermore, N-hydroxysulfonamide type nitroxyl donors may also have solubility problems that limit or prevent their use in oral or parenteral dosage forms. Thus, improved stability and solubility of N-hydroxysulfonamide type nitroxyl donors may be important before the donor can be used for therapeutic applications.

  In accordance with one aspect of the present disclosure, it has been found that cyclodextrins can be used to dramatically enhance the stability and / or solubility of N-hydroxysulfonamide type nitroxyl donors. Specifically, cyclodextrins reduce the formation of nitroxyl and sulfinic acid by-products (eg, compounds of formulas (100) and (101)) in pharmaceutical compositions during storage prior to administration to a patient. Or can be eliminated. The presence of cyclodextrin also allows some N-hydroxysulfonamide type nitroxyl donors to be stabilized at higher pH (e.g., between pH 5-6), thereby allowing for in section 4.4.2. For the reasons discussed, compositions with improved toxicological profiles are produced.

  In various embodiments, the at least one pharmaceutically acceptable additive comprises at least one cyclodextrin species. In certain embodiments, the cyclodextrin is a cyclic structure having glucose units connected by α (1-4) linkages. In another embodiment, the cyclodextrin is a β-cyclodextrin, a cyclic structure having seven glucose units linked by an α (1-4) linkage. In another embodiment, the cyclodextrin is chemically modified by derivatizing any combination of the three available hydroxyl groups of each glucopyranose unit.

In some embodiments where the pharmaceutically acceptable additive comprises at least one cyclodextrin species, the cyclodextrin is a sulfo (C ₁ -C ₆ ) alkyl ether derivative of β-cyclodextrin. In some of these embodiments, the cyclodextrin is from about six to about seven sulfo (C 1 _{-C 6)} beta-cyclodextrin sulfobutyl having an alkyl ether group per cyclodextrin molecule (C ₁ -C ₆ ) Alkyl ether derivatives. In various embodiments, the cyclodextrin is β-cyclodextrin sulfo (C ₁ -C ₆ ) having an average of about 6 to about 7 sulfo (C ₁ -C ₆ ) alkyl ether groups per cyclodextrin molecule. It is an alkyl ether derivative. In another such embodiment, the cyclodextrin is a sulfo (C ₁ -C ₆ ) alkyl ether derivative of β-cyclodextrin having ₆ or 7 sulfo (C ₁ -C ₆ ) alkyl ether groups per cyclodextrin molecule. It is.

In a series of specific embodiments where the pharmaceutically acceptable additive comprises at least one cyclodextrin species, the cyclodextrin is a sulfo (C ₃ -C ₅ ) alkyl ether derivative of β-cyclodextrin. In one such embodiment, the cyclodextrin is from about six to about seven sulfo per cyclodextrin molecule _(C 3 _{~C 5) β-} cyclodextrin sulfobutyl having an alkyl ether group _(C 3 _{~C 5)} alkyl ether Is a derivative. In various such embodiments, the cyclodextrin has an average per cyclodextrin molecule from about six to about seven sulfo _(C 3 ~C ₅₎ β- cyclodextrin sulfobutyl having an alkyl ether group (C ₃ -C ₅ ) Alkyl ether derivatives. In another such embodiment, the cyclodextrin is a sulfo (C ₃ -C ₅ ) alkyl ether derivative of β-cyclodextrin having 6 or 7 sulfo (C ₃ -C ₅ ) alkyl ether groups per cyclodextrin molecule. It is.

  In certain embodiments where the pharmaceutically acceptable additive comprises at least one cyclodextrin species, the cyclodextrin is a sulfobutyl ether derivative of β-cyclodextrin. In some of these embodiments, the cyclodextrin is a sulfobutyl ether derivative of β-cyclodextrin having from about 6 to about 7 sulfobutyl ether groups per molecule of cyclodextrin. In another such embodiment, the cyclodextrin is a sulfobutyl ether derivative of β-cyclodextrin having an average of about 6 to about 7 sulfobutyl ether groups per cyclodextrin molecule. In another such embodiment, the cyclodextrin is a sulfobutyl ether derivative of β-cyclodextrin having 6 or 7 sulfobutyl ether groups per cyclodextrin molecule.

  In certain embodiments where the pharmaceutically acceptable additive comprises at least one cyclodextrin species, the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin. In one such embodiment, the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having from about 6 to about 7 sulfo-n-butyl ether groups per cyclodextrin molecule. In another such embodiment, the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having an average of about 6 to about 7 sulfo-n-butyl ether groups per cyclodextrin molecule. In another such embodiment, the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having 6 or 7 sulfo-n-butyl ether groups per cyclodextrin molecule.

  In various specific embodiments, where the pharmaceutically acceptable additive comprises at least one cyclodextrin species, the cyclodextrin is at a physiologically compatible pH value, for example, in some embodiments a pH of about 5.0 to about 6.8, in some embodiments from about 5.5 to about 6.5, in some embodiments from about 5.7 to about 6.3, in some embodiments from about 5. From 8 to about 6.2, in some embodiments from about 5.9 to about 6.1, and in certain embodiments from about 6.0, it comprises a plurality of negative charges. In one such embodiment, the at least one pharmaceutically acceptable additive comprises CAPTISOL® cyclodextrin (Ligand Pharmaceuticals, La Jolla, Calif.).

  The molar ratio between the N-hydroxysulfonamide type nitroxyl donor and cyclodextrin present in the composition can be from about 0.02: 1 to about 2: 1. In certain embodiments, the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and cyclodextrin present in the composition can be from about 0.05: 1 to about 1.5: 1. it can. In certain embodiments, the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and cyclodextrin present in the composition can be from about 0.1: 1 to about 1: 1. In certain embodiments, the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and cyclodextrin present in the composition can be from about 0.5: 1 to about 1: 1. In certain embodiments, the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and cyclodextrin present in the composition can be from about 0.7: 1 to about 1: 1. In certain embodiments, the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and cyclodextrin present in the composition can be from about 0.1: 1 to about 0.8: 1. it can. In certain embodiments, the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and cyclodextrin present in the composition can be from about 0.1: 1 to about 0.6: 1. it can. In certain embodiments, the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and cyclodextrin present in the composition can be from about 0.2: 1 to about 1: 1. In certain embodiments, the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and cyclodextrin present in the composition can be from about 0.2: 1 to about 0.8: 1. it can. In certain embodiments, the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and cyclodextrin present in the composition can be about 0.4: 1 to about 0.8: 1. it can. In certain embodiments, the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and cyclodextrin present in the composition can be from about 0.4: 1 to about 0.6: 1. it can. In certain embodiments, the cyclodextrin is CAPTISOL®. To calculate the molar amount, CAPTISOL® is assumed to have an average molecular weight (MW) of 2163 g / mol.

  In embodiments in which the N-hydroxysulfonamide type nitroxyl donor is administered parenterally (eg, intravenously) as an aqueous composition, the cyclodextrin is about 0.001% cyclodextrin (w / v) to about It can be present in the composition within the range of 10% cyclodextrin (w / v). In some embodiments, cyclodextrin can be present in the composition in the range of about 0.005% cyclodextrin (w / v) to about 8% cyclodextrin (w / v). In certain embodiments, the cyclodextrin can be present in the composition in the range of about 0.010% cyclodextrin (w / v) to about 6% cyclodextrin (w / v). In certain embodiments, cyclodextrin can be present in the composition in the range of about 0.5% cyclodextrin (w / v) to about 8% cyclodextrin (w / v). In certain embodiments, cyclodextrin can be present in the composition in the range of about 1% cyclodextrin (w / v) to about 8% cyclodextrin (w / v). In certain embodiments, the cyclodextrin can be present in the composition in the range of about 2% cyclodextrin (w / v) to about 8% cyclodextrin (w / v). In certain embodiments, the cyclodextrin can be present in the composition in the range of about 2% cyclodextrin (w / v) to about 6% cyclodextrin (w / v). In certain embodiments, the cyclodextrin is CAPTISOL®.

  As described in Example 7, a composition comprising a nitroxyl donor and a cyclodextrin can be prepared as a concentrate at a specific pH. Such concentrates can be prepared by adding a nitroxyl donor to an aqueous cyclodextrin solution at a specific pH (eg, pH 4). This concentrate can then be diluted in a suitable aqueous solution (eg, buffer) and administered to the patient. Alternatively, a concentrate comprising nitroxyl donor and cyclodextrin can be lyophilized to form a powder. The lyophilized powder can be reconstituted in a suitable aqueous vehicle prior to administration.

4.5 Methods of Using the Compounds and Pharmaceutical Compositions of the Disclosure In one aspect, the disclosure provides a method of improving nitroxyl levels in vivo, in a patient in need thereof, in an effective amount of the book. A method is provided comprising the step of administering a compound or pharmaceutical composition disclosed herein. In various embodiments, the patient has, is suspected of having, or is at risk of having the condition in response to nitroxyl therapy.

  In certain embodiments, the disclosure provides a method of treating, preventing, or delaying the onset and / or occurrence of a condition, wherein the patient is identified as in need of such treatment, prevention, or delay. Comprising administering an effective amount of a compound or pharmaceutical composition disclosed herein. The identification of a patient in need thereof may be at the discretion of a physician, clinical staff, paramedic or other healthcare professional, and may be subjective (eg, opinion) or objective (eg, trial or It can be measured by a diagnostic method).

  Particular conditions encompassed by the methods disclosed herein include, but are not limited to, cardiovascular disease, ischemia / reperfusion injury, and pulmonary hypertension (PH).

4.5.1 Cardiovascular Disease In one embodiment, the disclosure provides a method of treating a cardiovascular disease in a patient in need thereof in an effective amount of a compound or medicament disclosed herein. A method is provided comprising the step of administering a composition.

  Examples of cardiovascular diseases and conditions that can be usefully treated with the compounds and compositions disclosed herein include cardiovascular diseases responsive to nitroxyl therapy, coronary artery occlusion, coronary artery disease (CAD), angina Disease, heart attack, myocardial infarction, hypertension, ischemic cardiomyopathy and infarction, pulmonary congestion, pulmonary edema, cardiac fibrosis, valvular heart disease, pericardial disease, congestive circulatory condition, peripheral edema, ascites, Chagas disease, Includes ventricular hypertrophy, heart valve disease, heart failure, diastolic heart failure, systolic heart failure, congestive heart failure, acute congestive heart failure, acute decompensated heart failure, and cardiac hypertrophy.

4.5.1.1 Heart Failure The nitroxyl donating compositions of the present disclosure can be used to treat patients suffering from heart failure. Heart failure can be of any type or form, including any heart failure disclosed herein. Non-limiting examples of heart failure include early stage heart failure, class I, II, III and IV heart failure, acute heart failure, congestive heart failure (CHF), and acute congestive heart failure. In one embodiment, the compounds and compositions of the present disclosure can be used to treat acute decompensated heart failure.

  In embodiments where the nitroxyl donating compositions of the present disclosure are used to treat patients suffering from heart failure, another active agent that treats heart failure can also be administered. In one such embodiment, the nitroxyl donor can be administered in combination with a positive inotropic agent such as a beta-agonist. Examples of beta-agonists include, but are not limited to, dopamine, dobutamine, isoproterenol, analogs of such compounds, and derivatives of such compounds. In another embodiment, the nitroxyl donor can be administered in combination with a beta-adrenergic receptor antagonist (also referred to herein as a beta-antagonist or beta-blocker). Examples of beta-antagonists include, but are not limited to, propranolol, metoprolol, bisoprolol, bucindolol, and carvedilol.

  As described in Example 3, a model of heart failure was used to evaluate the hemodynamic profile of compositions containing some of the longer half-life nitroxyl donors. As shown in FIG. 1 discussed in Example 3, the composition of the present disclosure produced a significant enhancement of inotropic and myocardial relaxation, and a modest decrease in blood pressure without tachycardia. Furthermore, the onset of significant hemodynamic effects was rapid (eg, within 1 hour), and for most of the compositions, almost maximal effects were achieved within 2 hours.

  The hemodynamic activity of the composition of the present disclosure is similar to a composition comprising a nitroxyl donor CXL-1020 when administered intravenously, but has a longer half-life than CXL-1020. The toxicological profile of the donor is significantly improved compared to the composition containing CXL-1020 (see Examples 5 and 6 and FIGS. 2-4). For example, the “Non-Observed Adverse Effect Levels (NOAEL)” of nitroxyl donors useful in the compositions of the present disclosure was substantially higher than the NOAEL for CXL-1020 (for an explanation of the NOAEL determination) See Example 5). In particular, the compound of formula (1) has the most advantageous toxicological profile among all N-hydroxysulfonamide type nitroxyl donors tested so far, at least 30 μg / kg / min. When administered intravenously at high concentrations, it has no adverse effect on clinical markers of inflammation (FIG. 2). In contrast, CXL-1020 begins to exhibit undesirable side effects at concentrations as low as 0.3 μg / kg / min.

4.5.1.2 Ischemia / Reperfusion Injury In another embodiment, the disclosed subject matter is a method of treating, preventing, or delaying the onset and / or occurrence of ischemia / reperfusion injury. There is provided a method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein.

  In certain embodiments, the method is for preventing ischemia / reperfusion injury. In certain embodiments, a pharmaceutical composition of the present disclosure is administered prior to the onset of ischemia. In certain embodiments, a pharmaceutical composition of the present disclosure is administered prior to a procedure in which myocardial ischemia may occur, such as angioplasty or surgery, such as coronary artery bypass graft surgery. In certain embodiments, a pharmaceutical composition of the present disclosure is administered after ischemia but before reperfusion. In certain embodiments, a pharmaceutical composition of the present disclosure is administered after ischemia and reperfusion.

  In another embodiment, a pharmaceutical composition of the present disclosure can be administered to a patient at risk for an ischemic event. In certain embodiments, a pharmaceutical composition of the present disclosure is administered to a patient who is at risk for a future ischemic event but does not currently have evidence of ischemia. Determining whether a patient is at risk for an ischemic event can be made by any method known in the art, such as by examining the patient or the patient's medical history. In certain embodiments, the patient has previously had an ischemic event. Thus, the patient may be at risk for an initial or subsequent ischemic event. Examples of patients at risk for an ischemic event include EKG with known hypercholesterolemia, ischemia (eg, T wave elevation or reversal, or ST segment elevation or depression in the appropriate clinical setting) Changes, abnormal EKG not associated with active ischemia, CKMB elevation, clinical evidence of ischemia (eg, compressive substernal chest pain or arm pain, shortness of breath, and / or hyperhidrosis), preexisting myocardial infarction Patients with history, elevated serum cholesterol, evidence lifestyle, evidence from partial coronary occlusion angiography, echocardiographic evidence of myocardial injury, or any other evidence of risk for future ischemic events included. Examples of ischemic events include, but are not limited to, neurovascular ischemia such as myocardial infarction (MI) and cerebrovascular stroke (CVA).

  In another embodiment, the subject of treatment is an organ to be transplanted. In certain embodiments, a pharmaceutical composition of the present disclosure can be administered prior to organ reperfusion in a transplant recipient. In certain embodiments, a pharmaceutical composition of the present disclosure can be administered prior to removal of an organ from a donor, for example, by a perfusion cannula used in the organ removal process. Where the organ donor is a living donor, such as a kidney donor, the compound or pharmaceutical composition of the present disclosure can be administered to the organ donor. In certain embodiments, a compound or pharmaceutical composition of the present disclosure is administered by storing an organ in a solution containing the compound or pharmaceutical composition. For example, a compound or pharmaceutical composition of the present disclosure is a University of Wisconsin “UW” solution (US Pat. No. 4) which is a solution comprising hydroxyethyl starch substantially free of ethylene glycol, ethylene chlorohydrin and acetone. , 798, 824), and the like. In certain embodiments, a pharmaceutical composition of the present disclosure that is administered reduces ischemia / reperfusion injury to organ tissue upon reperfusion in a recipient of a transplanted organ. In certain embodiments, the method reduces tissue necrosis (infarct size) in at-risk tissue.

  Ischemia / reperfusion injury can damage tissues other than myocardial tissue, and the disclosed subject matter includes methods of treating or preventing such damage. In various embodiments, the ischemia / reperfusion injury is non-myocardial. In certain embodiments, the method reduces damage due to ischemia / reperfusion in tissues of any part of the body other than the brain, liver, gastrointestinal tract, kidney, intestine, or myocardium. In another embodiment, the patient is at risk for such damage. Selection of a person at risk for non-myocardial ischemia can include determining the indicators used to assess the risk for myocardial ischemia. However, other factors may indicate risk for ischemia / reperfusion in other tissues. For example, surgical patients often experience ischemia associated with surgery. Thus, patients scheduled for surgery can be considered at risk for an ischemic event. The following risk factors for seizures (or a subset of these risk factors) include patient risk for brain tissue ischemia, hypertension, smoking, carotid stenosis, physical inactivity, diabetes, hyperlipidemia, Transient ischemic attacks, atrial fibrillation, coronary artery disease, congestive heart failure, past myocardial infarction, left ventricular dysfunction due to mural thrombus, and mitral stenosis may be demonstrated. Ingall, Postgrad. Med. 107 (6): 34-50 (2000). In addition, complications of untreated infectious diarrhea in the elderly can include myocardial, renal, cerebrovascular, and intestinal ischemia. Slotwiner-Nie et al., Gastroenterol. Clin. N. Amer. 30 (3): 625-635 (2001). Alternatively, patients can be selected based on risk factors for ischemic bowel, kidney and / or liver disease. For example, treatment may be initiated in elderly patients at risk for a hypotensive episode (such as blood loss due to surgery). Thus, patients exhibiting these indications would be considered at risk for ischemic events. In another embodiment, the patient has any one or more of the conditions listed herein, such as diabetes and hypertension. Other conditions that can lead to ischemia, such as cerebral arteriovenous malformations, may demonstrate the patient's risk for an ischemic event.

4.5.2 Pulmonary hypertension In another embodiment, the pharmaceutical composition of the present disclosure can be used to prevent or delay the onset and / or occurrence of pulmonary hypertension. In one such embodiment, the pharmaceutical composition of the present disclosure can be used to prevent or delay the onset and / or occurrence of pulmonary arterial hypertension (PAH).

  In another embodiment, the disclosure provides a method of reducing mean pulmonary arterial blood pressure (MPAP), wherein an effective amount of a compound or pharmaceutical composition disclosed herein is administered to a patient in need thereof There is provided a method comprising the steps of: In another embodiment, MPAP is reduced by up to about 50%. In another embodiment, MPAP is reduced by up to about 25%. In another embodiment, MPAP is reduced by up to about 20%. In another embodiment, MPAP is reduced by up to about 15%. In another embodiment, MPAP is reduced by up to 10%. In another embodiment, MPAP is reduced by up to about 5%. In another embodiment, the MPAP is reduced to about 12 mmHg to about 16 mmHg. In another embodiment, MPAP is reduced to about 15 mmHg.

4.6 Modes of Administration, Regimens, and Dose Levels The compounds and pharmaceutical compositions of this disclosure can be administered by parenteral (eg, subcutaneous, intramuscular, intravenous, or intradermal) administration. In certain embodiments, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of this disclosure are administered by intravenous infusion. In other embodiments, the compounds and pharmaceutical compositions of this disclosure can be administered by oral administration.

  When administering a pharmaceutical composition comprising a compound of the present disclosure, the dosage is expressed based on the amount of active pharmaceutical ingredient, i.e., the amount of the nitroxyl donor compound of the present disclosure present in the pharmaceutical composition. .

  For intravenous administration, the dose can be usefully expressed per unit time, either as a fixed amount per unit time or as an amount based on weight per unit time.

  In various embodiments, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of the present disclosure is at least about 0.1 μg / kg / min, at least about 0.2 μg / kg / min, at least about 0.1. 3 μg / kg / min, at least about 0.4 μg / kg / min, at least about 0.5 μg / kg / min, at least about 1 μg / kg / min, at least about 2.5 μg / kg / min, at least about 5 μg / kg / min Min, at least about 7.5 μg / kg / min, at least about 10 μg / kg / min, at least about 11 μg / kg / min, at least about 12 μg / kg / min, at least about 13 μg / kg / min, at least about 14 μg / kg / min Min, at least about 15 μg / kg / min, at least about 16 μg / kg / min, at least about 17 μg / kg / min, at least about 18 μg / kg Min, at least about 19 μg / kg / min, at least about 20 μg / kg / min, at least about 21 μg / kg / min, at least about 22 μg / kg / min, at least about 23 μg / kg / min, at least about 24 μg / kg / min, At least about 25 μg / kg / min, at least about 26 μg / kg / min, at least about 27 μg / kg / min, at least about 28 μg / kg / min, at least about 29 μg / kg / min, at least about 30 μg / kg / min, at least about 31 μg / kg / min, at least about 32 μg / kg / min, at least about 33 μg / kg / min, at least about 34 μg / kg / min, at least about 35 μg / kg / min, at least about 36 μg / kg / min, at least about 37 μg / min kg / min, at least about 38 μg / kg / min, at least about 39 μg / kg / min, In an amount of at least about 40 [mu] g / kg / min, are administered intravenously.

  In various embodiments, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of the present disclosure is about 100 μg / kg / min or less, about 90 μg / kg / min or less, about 80 μg / kg / min or less, About 70 μg / kg / min or less, about 60 μg / kg / min or less, about 50 μg / kg / min or less, about 49 μg / kg / min or less, about 48 μg / kg / min or less, about 47 μg / kg / min or less, about 46 μg / Kg / min or less, about 45 μg / kg / min or less, about 44 μg / kg / min or less, about 43 μg / kg / min or less, about 42 μg / kg / min or less, about 41 μg / kg / min or less, about 40 μg / kg / Min., About 39 μg / kg / min or less, about 38 μg / kg / min or less, about 37 μg / kg / min or less, about 36 μg / kg / min or less, about 35 μg / kg / min or less, about 34 μg / kg / min Hereinafter, about 33 μg / Kg / min or less, about 32 μg / kg / min or less, about 31 μg / kg / min or less, or about 30 μg / kg / min or less.

  In some embodiments, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure are from about 0.1 μg / kg / min to about 100 μg / kg / min, from about 1 μg / kg / min to About 100 μg / kg / min, about 2.5 μg / kg / min to about 100 μg / kg / min, about 5 μg / kg / min to about 100 μg / kg / min, about 10 μg / kg / min to about 100 μg / kg / min About 1.0 μg / kg / min to about 80 μg / kg / min, about 10.0 μg / kg / min to about 70 μg / kg / min, about 20 μg / kg / min to about 60 μg / kg / min, about 15 μg / min kg / min to about 50 μg / kg / min, about 0.01 μg / kg / min to about 1.0 μg / kg / min, about 0.01 μg / kg / min to about 10 μg / kg / min, about 0.1 μg / min kg / min to about 1.0 μg / kg / min, about 0.1 μg / kg / min to about 0 μg / kg / min, about 1.0 μg / kg / min to about 5 μg / kg / min, about 70 μg / kg / min to about 100 μg / kg / min, or about 80 μg / kg / min to about 90 μg / kg / min Administered intravenously in amounts ranging from

  In certain embodiments, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of this disclosure are from about 10 μg / kg / min to about 50 μg / kg / min, from about 20 μg / kg / min to about 40 μg / min. It is administered intravenously in an amount ranging from kg / min, from about 25 μg / kg / min to about 35 μg / kg / min, or from about 30 μg / kg / min to about 40 μg / kg / min. In certain embodiments, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of this disclosure is administered intravenously in an amount of about 20 μg / kg / min to about 30 μg / kg / min.

  In various embodiments, including various oral administration embodiments, the compounds or pharmaceutical compositions of the present disclosure may be administered as a single daily dose (QD) or, for example, twice daily (BID), daily It is administered according to a daily dosing regime on a weight basis, either multiple times (TID) or multiple divided doses administered four times a day (QID).

  In certain embodiments, the nitroxyl donating N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of the present disclosure is at least about 0.5 mg / kg / d, at least about 0.75 mg / kg / d, At least about 1.0 mg / kg / d, at least about 1.5 mg / kg / d, at least about 2 mg / kg / d, at least about 2.5 mg / kg / d, at least about 3 mg / kg / d, at least about 4 mg / d kg / d, at least about 5 mg / kg / d, at least about 7.5 mg / kg / d, at least about 10 mg / kg / d, at least about 12.5 mg / kg / d, at least about 15 mg / kg / d, at least about 17.5 mg / kg / d, at least about 20 mg / kg / d, at least about 25 mg / kg / d, at least about 30 mg / d g / d, at least about 35 mg / kg / d, at least about 40 mg / kg / d, at least about 45 mg / kg / d, at least about 50 mg / kg / d, at least about 60 mg / kg / d, at least about 70 mg / kg / d d, administered at a dose of at least about 80 mg / kg / d, at least about 90 mg / kg / d, or at least about 100 mg / kg / d.

  In certain embodiments, nitroxyl-donating N-hydroxysulfonamide-type nitroxyl donors useful in the pharmaceutical compositions of this disclosure are about 100 mg / kg / d or less, about 100 mg / kg / d or less, about 90 mg / kg. / D or less, about 80 mg / kg / d or less, about 80 mg / kg / d or less, about 75 mg / kg / d or less, about 70 mg / kg / d or less, about 60 mg / kg / d or less, about 50 mg / kg / d Hereinafter, it is administered at a dose of about 45 mg / kg / d or less, about 40 mg / kg / d or less, about 35 mg / kg / d or less, about 30 mg / kg / d or less.

  In various embodiments, the dose is about 0.001 mg / kg / d to about 10,000 mg / kg / d. In certain embodiments, the dose is about 0.01 mg / kg / d to about 1,000 mg / kg / d. In certain embodiments, the dose is about 0.01 mg / kg / d to about 100 mg / kg / d. In certain embodiments, the dose is about 0.01 mg / kg / d to about 10 mg / kg / d. In certain embodiments, the dose is about 0.1 mg / kg / d to about 1 mg / kg / d. In certain embodiments, the dose is less than about 1 g / kg / d.

  In certain embodiments, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure have any lower end of the range of about 0.1 mg / kg / day to about 90 mg / kg / day. The upper end of the range is from about 1 mg / kg / day to about 100 mg / kg / day (eg, from about 0.5 mg / kg / day to about 2 mg / kg / day in another series, In embodiments, it is administered in a dose range that is any amount from about 5 mg / kg / day to about 20 mg / kg / day.

  In certain embodiments, an N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of this disclosure is administered from about 3 to about 3 times daily (QD) to 3 times daily (TID). It is administered at a dose range of 30 mg / kg.

  In certain embodiments, a compound or pharmaceutical composition of the present disclosure is administered as a single daily dose (QD) or, for example, twice daily (BID), three times daily (TID), or four times daily. Administered according to a constant (ie, non-weight basis) dosing regimen in either multiple divided doses administered (QID).

  In various embodiments, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of the present disclosure is at least about 0.01 grams / day (g / d), at least about 0.05 g / d, at least about 0.1 g / d, at least about 0.5 g / d, at least about 1 g / d, at least about 1.5 g / d, at least about 2.0 g / d, at least about 2.5 g / d, at least about 3.0 g / d d, or at a dose of at least about 3.5 g / d.

  In various embodiments, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of the present disclosure can be about 5 g / d or less, about 4.5 g / d or less, about 4 g / d or less, about 3.5 g. / D or less, about 3 g / d or less, about 2.5 g / d or less, or about 2 g / d or less.

  In certain embodiments, N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions of this disclosure are administered at a dose of about 0.01 grams per day to about 4.0 grams per day. . In certain embodiments, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of the present disclosure is any amount at the lower end of the range from about 0.1 mg / day to about 400 mg / day, Can be administered in doses where the upper end is any amount from about 1 mg / day to about 4000 mg / day. In certain embodiments, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of this disclosure is administered at a dose of about 5 mg / day to about 100 mg / day. In various embodiments, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical compositions of this disclosure is administered at a dose of about 150 mg / day to about 500 mg / day.

  Dosage intervals for parenteral or oral administration can be adjusted according to the needs of the patient. Slow release or depot formulations can be used when there is a longer interval between administrations.

  The N-hydroxysulfonamide type nitroxyl donors useful in the pharmaceutical compositions disclosed herein disclosed herein can be administered before, substantially simultaneously with, or after administration of the additional therapeutic agent. . This dosing regimen may include pre-treatment and / or co-administration with additional therapeutic agents. In such cases, the N-hydroxysulfonamide type nitroxyl donor useful in the pharmaceutical composition of the present disclosure and the additional therapeutic agent can be administered simultaneously, separately or sequentially.

  Examples of administration regimes include, but are not limited to, sequential administration of each compound, pharmaceutical composition or therapeutic agent, and substantially simultaneous administration of each compound, pharmaceutical composition or therapeutic agent (eg, in a single unit dosage form). ), Or co-administration in multiple individual unit dosage forms for each compound, pharmaceutical composition or therapeutic agent.

  The “effective amount” or “dose” (“dose level”) depends on various factors such as the particular mode of administration selected, the dosage regimen, the compounds and pharmaceutical compositions, and the particular condition being treated and the patient. It will be understood by those skilled in the art. For example, appropriate dosage levels are determined by the specific N-hydroxysulfonamide type nitroxyl donor activity, elimination rate and potential toxicity useful for the pharmaceutical composition of the present disclosure used, the age, weight, It can vary depending on general health, sex and diet, frequency of administration, other therapeutic agents co-administered, and the type and severity of the condition.

4.7 Kits Comprising a Compound or Pharmaceutical Composition The present disclosure provides a kit comprising a compound or pharmaceutical composition disclosed herein. In certain embodiments, the kit comprises a compound or pharmaceutical composition disclosed herein, and a pharmaceutically acceptable liquid excipient, each in dry form.

  Either the dry form of the compound or the dry form of the pharmaceutical composition comprises no more than about 2.0 wt% water, no more than about 1.5 wt% water, no more than about 1.0 wt% water, 5 wt% or less, about 0.3 wt% or less, about 0.2 wt% or less, about 0.1 wt% or less, about 0.05 wt% or less, Contains no more than 03 wt% water, or no more than about 0.01 wt% water.

  Pharmaceutically acceptable liquid excipients are known in the art and include, but are not limited to, sterile water, saline solution, aqueous dextrose, glycerol, glycerol solution and the like. Other examples of suitable liquid excipients are Nairn, "Solutions, Emulsions, Suspensions and Extracts," pp. 721-752 in Gennaro, Ed., Remington: The Science and Practice of Pharmacy, 20th Ed. (Lippincott Williams & Wilkins, Baltimore, MD, 2000).

  In one embodiment, the kit further comprises instructions for using the compound or pharmaceutical composition. The instructions can be in any suitable form, such as a document form or an electronic form. In another embodiment, the instructions may be document instructions. In another embodiment, the instructions are on an electronic storage medium (eg, magnetic diskette or optical disk). In another embodiment, the instructions include information regarding the compound or pharmaceutical composition and how to administer the compound or pharmaceutical composition to a patient. In another embodiment, the instructions are selected from the methods of use disclosed herein (eg, cardiovascular disease, ischemia / reperfusion injury, pulmonary hypertension, and other conditions that respond to nitroxyl therapy). Treatment, prevention and / or delay of the onset and / or occurrence of a condition to be caused).

In another embodiment, the kit further comprises appropriate packaging. If the kit contains more than one compound or pharmaceutical composition, the compounds or pharmaceutical compositions may be combined in separate containers or in one container if cross-reactivity and shelf life are allowed. And can be packaged patiently.
(Example)

  The following examples are presented for illustrative purposes and should not serve to limit the scope of the disclosed subject matter.

5.1 Example 1: HNO production determined by quantifying N ₂ O Nitrous oxide (N ₂ O), produced by HNO dimerization and dehydration, is the most common marker of nitroxyl production ( Fukuto et al., Chem. Res. Toxicol. 18: 790-801 (2005)). However, nitroxyl can also provide products that are partially inactivated by oxygen and do not produce N ₂ O (Mincione et al., J. Enzyme Inhibition 13: 267-284 (1998) and Scozzafava et al. , J. Med. Chem. 43: 3677-3687 (2000)). As a standard, either nitrous oxide gas or Angeli salt (AS) was used, and the relative amount of N ₂ O released from the disclosed compounds was examined by gas chromatography (GC) headspace analysis.

The procedure for determining the relative amount of N ₂ O released from the disclosed compounds is as follows. GC was performed on an Agilent gas chromatograph equipped with a split injector (split ratio 10: 1), a micro-electron capture detector, and an HP-MOLSIV 30 m × 0.32 mm × 25 μm molecular sieve capillary column. Helium was used as the carrier (4 mL / min) gas and nitrogen was used as the make-up (20 mL / min) gas. The injector oven and detector oven were maintained at 200 ° C. and 325 ° C., respectively. All nitrous oxide analyzes were performed in a column oven maintained at a constant temperature of 200 ° C.

  All gas injections were performed using an automated headspace analyzer. The pressure of the vial was 15 psi. The analyzer sample oven, sampling valve, and transfer line were maintained at 40 ° C., 45 ° C., and 50 ° C., respectively. Oven stabilization, vial pressurization, loop filling, loop equilibration, and sample injection times were 1.00 min, 0.20 min, 0.20 min, 0.05 min, and 1.00, respectively. Minutes.

  All determinations used a nominal 20 mL headspace vial with a pre-measured volume for sample homogeneity (actual vial volume varied with relative standard deviation ≦ 2.0% (n = 6)). Average vial volume for this batch is capped and sealed with an empty (ie, air-filled) vial capped and sealed using a known density of deionized water from 6 randomly selected vials The weight difference from the deionized water filled vials was calculated and then determined by taking the average. Blanks were prepared by sealing and capping two vials and then purging each with a gentle stream of argon for 20 seconds. Nitroxyl standards were prepared by sealing and capping four vials, then purging from the gas cylinder with a gentle stream of 3000 ppm nitroxyl standard each for 1 minute each.

  CXL-1020 (N-Hydroxy-2-methanesulfonylbenzene-1-sulfonamide) “standard” was measured in 2 mL, accurately weighing 10 ± 0.5 mg of CXL-1020 into 4 mL vials. It was prepared by adding to Using an autopipette, add 1 mL of argon purged anhydrous DMF (Sigma-Aldrich) to each 4 mL vial to make a CXL-1020 stock solution for each sample, cap these vials, shake and / or Sonication was performed to ensure complete dissolution during visual observation. Using an autopipette, a 20 mL vial was charged with 5 mL PBS (purged with argon for at least 30 minutes prior to use), purged with argon for at least 20 seconds, and sealed with a rubber septum. Using a 50 μL syringe, 50 μL of CXL-1020 stock solution was injected into each of the 20 mL vials containing PBS.

  Samples were prepared as follows. In duplicate, each sample 18 ± 1 mg was accurately weighed into each 4 mL vial. Using an autopipette, add 1 mL of argon purged anhydrous DMF to each 4 mL vial to make a stock solution of the sample for each sample, cap these vials and shake and / or sonicate them during visual observation. To ensure complete dissolution of the sample. Using an autopipette, a 20 mL vial was charged with 5 mL PBS (purged with argon for at least 30 minutes prior to use), purged with argon for at least 20 seconds, and sealed with a rubber septum. These vials were equilibrated in a dry block heater at 37 ° C for at least 10 minutes. Thereafter, a 50 μL syringe was used to inject 50 μL of the sample stock solution into each of the 20 mL vials containing PBS. These vials are then placed in a dry block heater at 37 ° C., the sum of the time spent in the dry block heater and the time spent in the automated headspace analyzer oven prior to sample injection is the desired incubation time. Held for a time equal to.

The order of automatic injection was as follows. Blank Repeat 1, Blank Repeat 2, N ₂ O Standard Repeat 1, N ₂ O Standard Repeat 2, CXL-1020 Standard Repeat 1, CXL-1020 Standard Repeat 2, Sample 1 Repeat 1, sample 1 repeat 2, sample 2 repeat 1, sample 2 repeat 2, etc. N ₂ O standard repeat 3 and N ₂ O standard repeat 4 at the end. Using the data thus determined, an EXCEL spreadsheet is used to calculate the relative N ₂ O yield as a percentage of each incubation time for each sample. The results obtained are shown in Table 3. “-” Indicates that the result was not obtained.

For the compound of formula (99), the determination is as described above, except that the enzyme activated sample was also prepared as follows. (I) 50 mg of porcine liver esterase (PLE, E3019-20KU, crude product, Sigma-Aldrich) is accurately weighed into a 20 mL headspace vial, (ii) 5 mL of anhydrous PBS purged with argon using an autopipette (Iii) Cap the vial and shake to ensure complete dissolution upon visual observation. (Iv) Replace the nitroxyl donor sample with 5 mL of PBS. Prepare as disclosed above, and add (v) 250 μmL of PLE stock solution into a 20 mL vial prior to sample addition using an autopipette. The order of automatic injection is as follows. Blank Repeat 1, Blank Repeat 2, N ₂ O Standard Repeat 1, N ₂ O Standard Repeat 2, CXL-1020 Standard Repeat 1, CXL-1020 Standard Repeat 2, Sample 1 ( Repeat 1 with no PLE), repeat 2 with sample 1 (without PLE), repeat 1 with sample 1 (with PLE), repeat 2 with sample 1 (with PLE), repeat 1 with sample 2 (without PLE), sample 2 ( repeat 2 without PLE), sample 2 repeats 1 (PLE-containing), sample 2 (such as iteration 2 of PLE-containing), _{N 2} O standard iteration 3 of the end, and _{N 2} O in the standard iterative 4 .

Another procedure for determining the relative amount of N ₂ O released from the disclosed compounds is as follows. GC is performed on a Varian CP-3800 instrument equipped with a 1041 manual injector, an electron capture detector, and a 25m 5Å molecular sieve capillary column. Grade 5.0 nitrogen is used as both carrier (8 mL / min) and makeup (22 mL / min) gas. The injector oven and detector oven are maintained at 200 ° C. and 300 ° C., respectively. All analyzes of nitrous oxide are performed in a column oven maintained at a constant temperature of 150 ° C. All gas injections are performed using a 100 μL gas tight syringe with sample lock. For sample homogeneity, samples are prepared in amber 15 mL headspace vials with a pre-measured volume (actual vial volume ranges from 15.19 to 15.20 mL). The vial was charged with 5 mL of PBS containing diethylenetriaminepentaacetic anhydride (DTPA), purged with argon and sealed with a rubber septum. These vials are equilibrated in a dry block heater at 37 ° C. for at least 10 minutes. A 10 mM stock solution of AS is prepared in 10 mM sodium hydroxide, and a solution of the nitroxyl donor in either acetonitrile or methanol is prepared and used immediately after preparation. 50 μL from these stock solutions are introduced into individually heat equilibrated headspace vials using a 100 μL gas tight syringe with sample lock to obtain a final substrate concentration of 0.1 mM. The substrate is then incubated for 90 minutes or 360 minutes. Next, the head space (60 μL) is sampled and injected into the GC apparatus five times in succession using a gas tight syringe with a sample lock. This procedure is repeated for two or more vials per donor.

5.2 Example 2: In vitro stability of nitroxyl donors in plasma Certain compounds from Tables 1 and 2, and CXL-1020, were stabilized in phosphate buffered saline (PBS) and plasma. Tested for sex. The assay system consists of (i) PBS at pH 7.4 or plasma from rats, dogs or humans (at least 3 male donors and pooled), and (ii) for tests performed in plasma Anticoagulant (sodium heparin or sodium citrate) was included. Each test compound (5 μM) was incubated with THERMOMIXER® in PBS or plasma at 37 ° C. with shaking. Three samples (n = 3) were taken at 7 sampling time points: 0, 10, 30, 60, 90, 180 and 360 minutes, respectively. Samples were immediately mixed with 3 volumes of acetonitrile containing 1% formic acid and an internal standard to complete the reaction (ie 3 volumes of PBS or plasma). AB SCIEX API 3000 LC-MS / MS analysis of test compounds was performed without a standard curve. Using the peak area response ratio, the half-life (T _1/2 ) of the test compound was determined from the graph of percent residual value. The determined half-life is shown in Table 4. For compounds tested multiple times, the values presented in the table are the average of repeated assays.

  When determining the half-life of a compound of formula (99), a stock solution of porcine liver esterase (PLE) is added to PBS or plasma prior to the addition of the compound.

5.3 Example 3: Hemodynamic efficacy of nitroxyl donor in normal and heart failure dogs (tachycardia pacing model)
5.3.1 Materials and Methods The cardiovascular effects of nitroxyl donors were examined by pressure-volume (PV) curve (loop) analysis in conscious beagle dogs inhibited by laces. Animals were allowed free access to drinking water and commercial dog food under standard laboratory conditions. Fluorescent lighting was provided by an automatic timer for approximately 12 hours per day. Occasionally, the dark cycle was interrupted intermittently for work related to the study. Temperature and humidity were monitored and recorded daily and maintained to a maximum between 64 ° F and 84 ° F and between 30% and 70%, respectively. Dogs were accustomed for a period of at least one week before surgery. After surgery and recovery, animals were accustomed to string suppression for up to 4.5 hours. The animals were fasted overnight before surgery.

Surgical Procedure Anesthesia For infusion of anesthetics, an indwelling venous catheter was placed in the peripheral vein (eg, cephalic skin). General anesthesia was induced by intravenous (bolus administration) of buprenorphine (approximately 0.015 mg / kg) followed by intravenous bolus administration of propofol (approximately 6 mg / kg). In addition, prophylactic antibiotics (cefazoline 20-50 mg / kg by iv) were given at the time of induction. To maintain the PaCO ₂ value within the physiological range, a cuffed tracheal tube is placed and mechanically ventilated with 100% O ₂ via a veterinary ventilator for animals (tidal volume of about 12. About 12 breaths / min with 5 mL / kg). Anesthesia was maintained by inhalation of isoflurane (1% -3%).

Placement of cardiovascular equipment Once stable (surgical) levels of anesthesia are established, left thoracotomy is performed (strict aseptic conditions), each animal is placed with a sono-micrometer crystal over time, and the left ventricle (LV) ) Size / volume was obtained. In addition, a liquid-filled catheter and a solid-state monometer were attached to the left ventricle for pressure monitoring. A liquid-filled catheter was placed in the right ventricle (RV) and aorta (Ao) for pressure monitoring / test article administration. A hydrostatic (In-Vivo Metrics) occluder is placed / fixed around the inferior vena cava (IVC) to allow its stenosis control to create an LV pressure-volume curve during an isometric self-regulation did. The catheter / wire was aseptically penetrated between the scapulae and exited. To prevent both clot formation and bacterial growth, liquid-filled catheters were flushed with locking solution periodically (at least once a week) (2-3 mL taurolidine-citrate solution, TCS) during the study. -04; Access Technologies).

Pacemaker Implantation After placement of the cardiovascular device, the right jugular vein was carefully exposed and cannulated with a bipolar pacing lead / catheter (CAPSUREFIX® Novus; Medtronic). Under fluoroscopy, the pacing lead was placed in the right ventricle in the antegrade direction and actively attached (screwed) to the tip of the endocardium. The proximal end of this lead was secured to a pacing device (Kappa900; Medtronic). Subsequently, a pacemaker was placed / fixed in the subcutaneous pocket of the neck.

  A bipolar pacing wire was fixed in the center of the myocardium of the right ventricle, taking into account that the heart was exposed by thoracotomy. The pacing lead was passed between / exposed between the scapulae and used in connection with an external impulse generator / pacemaker. The implanted endocardial pacemaker was used as a backup to an external / epicardial pacemaker.

Recovery Before closing the chest from the thoracotomy, a chest tube was attached to drain any fluid and / or gas that accumulated from the surgical procedure. The tube was aspirated twice a day until the amount of liquid removed was less than 35 mL per aspiration after approximately 24 hours. The chest tube was then removed.

  All animals received a prophylactic antibiotic (cefazoline 20-50 mg / kg by iv) and pain medication (approximately 0.2 mg / kg meloxicam by iv). Additional anesthetics were also administered as needed, including fentanyl patches (25-50 mcg / hour). All surgical incisions were overlaid and closed. The underlying muscle tissue was closed with absorbable sutures and the skin was closed with staples.

  After surgery, the animals were allowed to recover for at least 14 days. After surgery, cephalexin (20-50 mg / kg) was orally administered BID for at least 7 days and meloxicam (0.1 mg / kg) was orally or subcutaneously administered SID for at least 2 days. Throughout the recovery period, the animals were observed daily for routine signs of recovery and the site of the wound was observed for any signs of possible infection. The animals receiving pain, distress and / or infection received the attention of the designated veterinarian and principal investigator. Skin incision staples were not removed for at least 7 days after surgery.

Induction of heart failure After recovery from surgery and / or a sufficient washout period from administration with a nitroxyl donor, the animals are intended to cause left ventricular dysfunction / remodeling consistent with heart failure syndrome for 3 weeks. High frequency drive pacing (210 ppm) protocol was applied. Briefly, the ventricles were paced asynchronously and continuously at 210 beats per minute (bpm) via an implanted pacemaker / right ventricular lead. After pacing for approximately 3 weeks, left ventricular remodeling (and induction of heart failure) is echocardiographic (eg, ejection fraction EF decreases from about 60% to a target of about 35%. Left ventricular LV dilation) and Confirmed by both changes in neuronal fluid (eg, N-terminal pro-brain natriuretic peptide (NT proBNP) is elevated to about 300 pM / L to above 1800 pM / L). Echocardiograms and blood samples were collected in the absence of pacing (at least 15 minutes).

5.3.2 Results Assessment of hemodynamic efficacy Animals (normal or heart failure) are treated with vehicle (control) and nitroxyl donor (CXL-1020 or formula (1), (2), (83), (84) or (Any of the compounds in (85)) were studied during treatment with both. During each dosing period, conscious animals suppressed with string were continuously monitored for up to 2-3 hours. After hemodynamic stabilization, vehicle injection was started. Immediately thereafter, the left ventricular preload was rapidly reduced by brief vena cava occlusion (temporary dilation of the vascular occluder) to generate a family of pressure-volume curves / loops. Up to three occlusions were performed to restore hemodynamics between each study. Vehicle infusion was continued and another set of (baseline) hemodynamic data was collected 30 minutes later. After collecting baseline hemodynamic data, infusion of the nitroxyl donor compound to be tested is initiated and up to 4 selected from 30, 60, 90, 120 and 180 minutes after initiation of vehicle / test compound infusion. At time points, hemodynamic type / function parameters were obtained / implemented. For placebo or time control treatment groups, each animal received an appropriate placebo infusion for up to 180 minutes. In all cases, the test compound was delivered at a constant intravenous infusion rate of 1 mL / kg / hr and compared at a molar equivalent or approximately two thirds of the molar equivalent dose.

  The left ventricular pressure and volume data obtained were analyzed in order to generate a relationship representing the myocardial systolic state and energy state. Systolic blood pressure (SAP), diastolic blood pressure (DAP), and mean arterial blood pressure (MAP) were collected. Pressure (ESP, EDP, dP / dt max / min, relaxation time constant-tau [based on single exponential decay with non-zero asymptote]) and volume (end systolic volume (ESV), end diastolic volume ( The left ventricular mechanical and / or geometric index was obtained from the signal of (EDV), stroke output (SV)). In addition, the following measurements were of a type from left ventricular pressure-volume data (PV loop) that occurred during a short preload drop. Pressure volume area (PVA) and stroke work (SW), end systolic blood pressure volume relationship (ESPVR) and end diastolic blood pressure volume relationship (EDPVR), and relationship between end systolic blood pressure and stroke volume (aortic elasticity Rate (Ea)). Representative data from studies of normal and heart failure dogs are shown in Tables 5 and 6. Representative data for heart failure dogs is also shown in FIG. A decrease in SVR (total peripheral vascular resistance) correlates with vasodilation.

  For example, the results in FIG. 1 indicate that the compounds of formulas (1), (2), (83), (84) and (85) have hemodynamic activity equivalent to CXL-1020 in both normal and failing canine models. It is demonstrated to have.

5.4 Toxicological studies with nitroxyl donors

5.4.1 Example 4: In vivo test with CXL-1020 Up to 90 μg during the in vivo test of CXL-1020 (N-hydroxy-2-methanesulfonylbenzene-1-sulfonamide), a nitroxyl donor. A 14-day study was conducted that evaluated tolerability in dogs treated by continuous infusion of CXL-1020 at a dose of / kg / min. This initial study found that CXL-1020 was tolerated when administered at a dose of 60 μg / kg / min. However, unexpectedly, at a dose of 60 μg / kg / min, a clinicopathological change consistent with the inflammatory process reflected in changes in clinicopathological markers of inflammation was observed. To further investigate this undesirable side effect, a 14-day follow-up study was initiated in dogs. This follow-up study had to be terminated after only 4 days due to the appearance of other undesirable side effects: considerable swelling in the hind legs of dogs with surgically implanted infusion catheters that sometimes interfered with normal leg function And unexpected occurrences of inflammation; skin discoloration of the groin; decreased activity; inappetance; and, in the highest dose group, cold skin when touched.

  An exploratory study of a series of 72-hour continuous infusions was conducted over the next 6 months to determine the cause of inflammation and hind limb swelling. The results of those studies indicate that CXL-1020 is 0.03 μg in dogs when administered in a pH 4 formulation with a 1: 1 molar ratio of CXL-1020: CAPTISOL® diluted in 5% dextrose in water. It has been shown to cause clinicopathological changes consistent with inflammatory processes at doses greater than / kg / min. Vascular inflammation was observed around the insertion site of the catheter into the femoral vein (15 cm upstream from the catheter tip), at the catheter tip, and downstream from the catheter tip. The site of catheter insertion, the first site of inflammation, caused swelling of the hind legs of the dog and inflammation observed in early follow-up studies. Increasing the pH of the infusate from 4 to 6 reduced inflammation and improved the inflammation profile by approximately 3-fold (see Figure 4). However, rather undesirable side effects were still demonstrated when CXL-1020 was administered in dogs at doses of 3 μg / kg / min and higher.

  To avoid side effects associated with the catheter insertion site and to evaluate whether vascular inflammation is due to the design of the implanted catheter, a percutaneous catheter placed in the peripheral (cephalic) vein was used in dogs, 24 A continuous infusion study of time was conducted. Significant edema was observed at the top of the forelimbs downstream from the catheter tip 6 hours after injection. Twenty-four hours after infusion, clinicopathological changes similar to those observed in previous studies using an implanted central catheter were detected. Similarly, a microscopic pathology was also detected that showed severe thrombophlebitis at the catheter tip, with a progressive reduction in severity downstream from the catheter tip.

  Longer-term studies were conducted in healthy volunteers to determine whether local phlebitis occurs in humans at longer doses. Longer-term studies will be followed by a continuous 24-hour infusion of CXL-1020 at a dose of 10, 20 and 30 μg / kg / min into a cohort of 10 volunteers, including safety assessments between each cohort Including a dose escalation study. Each cohort includes 2 active and 8 active treatments, including 1 active treatment and 1 placebo-treated sentinel pair, followed by 1 placebo and 7 active treatments Made up of a group. Infusion was via a percutaneous catheter inserted into the forearm vein. The catheter was changed to the opposite arm 12 hours after injection. A 24 hour dose of 10 μg / kg / min was found to be well tolerated. In the second cohort administered a dose of 20 μg / kg / min for 24 hours, there were no adverse findings in 2 placebo-treated volunteers, but in all 8 subjects, mild, consistent with injection site phlebitis There were findings (clinical signs and / or changes in clinical pathology). Based on these results, longer-term safety studies were stopped.

  An exploratory study was continued to determine the cause of the undesirable side effects of a more but still clinically desirable dose of CXL-1020. Studies conducted with CXL-1020 by-product, a moiety remaining after nitroxyl donation, were negative, and the side effects of CXL-1020 were either the parent compound CXL-1020 or HNO produced therefrom. It was shown to be due to. Studies were conducted using an alternative nitroxyl donor that is structurally unrelated to CXL-1020 but has a similar half-life (about 2 minutes half-life) for nitroxyl donation. In all cases, local vascular side effects at the catheter tip were observed. These results suggested that inflammation was caused by nitroxyl released rapidly from a short half-life nitroxyl donor.

5.4.2 Example 5: Longer half-life N-hydroxysulfonamide type nitroxyl donor has improved toxicological profile compared to CXL-1020 in male and female beagle dogs Carried out. Animals were allowed free access to drinking water and commercial dog food under standard laboratory conditions. At the time indicated by the study protocol, animals were fasted prior to collection of blood samples. Fluorescent lighting was provided by an automatic timer for approximately 12 hours per day. Occasionally, the dark cycle was interrupted intermittently due to research-related activities. Temperature and humidity were monitored and recorded daily to maintain a maximum between 64 ° F and 84 ° F and between 30% and 70%, respectively. Dogs were accustomed for a period of at least one week. During this period, animals were weighed weekly and observed for any signs of general health and disease. These animals were accustomed to wearing jackets for at least 3 days prior to dose administration. In addition, these animals were also accustomed to wearing an Elizabeth collar (e-color) during the habituation period of wearing the jacket.

Surgical and Dosing Procedures Animals were catheterized on the day prior to dose administration. A percutaneous catheter was placed in the cephalic vein at the distal part of the elbow (using aseptic technique and sterile dressing). The animals were allowed to move freely in cages during continuous infusion dose administration. To facilitate continuous infusion dose administration, the peripheral catheter was connected to an expansion device that passed under the dog's jacket and then connected to a tether infusion system. To prevent the animal from touching / removing the percutaneous catheter placed in the periphery, the catheter treatment site is bandaged using a Vet Wrap and the e-color is applied to the animal during the treatment (ie, during the catheter treatment period). Attached. During the pre-treatment period, 0.9% sodium chloride for injection, United States Pharmacopeia (saline) is continuously infused into the venous catheter at a rate of approximately 2-4 mL / hr to facilitate catheter patency. Maintained. Prior to dosing, the infusion system was pre-filled with each dosing solution (slow bolus infusion) to ensure that dosing started as soon as the infusion pump started. The injection line was connected to a reservoir containing a control or test compound and the injection started. The test composition was infused continuously at a given constant infusion rate (1 or 2 mL / kg / hr) for 24 hours and compared at a molar equivalent dose.

Clinical observations, clinical pathology, and microscopic pathology Detailed clinical examinations of each animal are performed twice a day, and blood samples for thermometry and clinical pathology are pre-dose and 6 hours after the start of composition infusion. Collected from all animals at 12 hours, 24 hours and 72 hours. At the end of the study, at the scheduled dissection, all animals were euthanized and a full anatomical examination was performed. Selected tissues were collected and fixed and stored for possible future microscopic examination. The cephalic vein containing the infusion catheter was incised along the brachiocephalic vein in a non-scratching manner and examined along its entire length. The position of the catheter tip on the non-fixed specimen was marked. After fixation, the specimen is cut out and processed into a slide, and the catheter tip and both the proximal and distal portions of the catheter tip (ie, 1 cm distal portion of the catheter tip, catheter tip, and 1, 5 of the catheter tip). Transverse tissue sections representing peripheral tissues (10, 15, and 20 cm proximal) were obtained. With respect to the catheter tip, “proximal” was defined as closer to the heart, and “distal” was defined as far from the heart.

Safety Assessment Clinicopathological changes consistent with inflammatory syndromes have been found in several doses of compounds of formulas (1), (2), (83), (84), (85), (86), and CXL- Observed at 1020. Each compound was formulated with CAPTISOL® (7% w / v) in sterile pH 4 water. The most sensitive biomarkers of inflammation are: (1) white blood cell count (WBC, obtained as (white blood cell count) / μL by multiplying the value at the right end of FIG. 2 by 103), (2) fibrinogen concentration (FIG. 2 And (3) C-reactive protein (CRP) concentration (given in mg / L at the right end of FIG. 2). The severity of the change depended on the compound itself and the rate at which the compound was administered (Figure 2). In FIG. 2, according to the right edge of the figure, scores ranging from 0 (low severity) to 2 (high severity) were assigned to each of these inflammation biomarkers. A cumulative score was calculated from the sum of these marker scores. The NOAEL, expressed in molar equivalent dose (μg / kg / min) to CXL-1020, determined based on these clinicopathological markers is shown in Table 7.

  For CXL-1020, significant increases in WBC, fibrinogen and CRP were observed even at concentrations as low as 0.03 μg / kg / min. Compounds with longer half-life of formulas (1), (2), (83), (84), (85) and (86) all have significantly higher doses of NOAEL than CXL-1020 . The compounds of formula (1) have the most advantageous toxicological profile and show no adverse effects even at doses as high as at least 20 μg / kg / min. This represents an improvement over 660 times that of the compound of formula (1) compared to CXL-1020.

  Taken together, these findings suggest that CXL-1020 infusion causes an inflammatory syndrome that is substantially alleviated by using the longer half-life nitroxyl donor of the present disclosure.

  These findings suggest that vascular toxicity associated with CXL-1020 upstream of the catheter tip, downstream of the catheter tip, and in certain situations, is due to local inflammation caused by nitroxyl release. It was done. Furthermore, it was hypothesized that inflammation could be significantly reduced at these sites using a longer half-life nitroxyl donor. This is confirmed by detailed histopathological examination of the vascular structure at the site inserted into the femoral vein (15 cm distal part of the catheter tip) along the catheter in the direction of the catheter tip and 20 cm downstream from the tip. Obtained by evaluating the body. Microscopic pathological findings of edema, bleeding, vascular inflammation and perivascular inflammation were determined at specific doses of nitroxyl donor.

  FIG. 3 illustrates a “heat map” showing the aggregated score of pathological findings by microscopy, in which the severity of vascular inflammation, bleeding, thrombus and vascular degeneration / regeneration is measured by the vascular structure described above. Were scored in sections. The findings of (1) edema, (2) vascular inflammation and perivascular inflammation, and (3) bleeding started from 1 cm distal (upstream) from the catheter tip and advanced 20 cm proximal (downstream) from the catheter tip The blood vessel sections were scored (0 = within normal range, 1 = minimum, 2 = mild, 3 = moderate, 4 = severe selected values). The aggregation score was calculated from the sum of these findings scores. In FIG. 3, the cumulative histological assembly score ranges from 0-2 (low severity) to 11-12 (high severity). It was observed that the severity of microscopic changes and the distance from the catheter tip where they were detected depended on the nitroxyl donor itself and the rate at which the nitroxyl donor was administered. The NOAEL values determined on the basis of these microscopic pathological markers for a series of nitroxyl donors expressed in molar equivalent doses (μg / kg / min) to CXL-1020 are shown in Table 8.

  These findings indicate that longer half-life nitroxyl donors (eg, compounds of formulas (83), (84), (85) and (86)) were substantially improved compared to CXL-1020. Having a toxicological profile is shown in Table 8. The side effect profile at any dose decreased in severity as a function of distance from the catheter tip, and the severity of vascular side effects decreased with decreasing dose. These findings confirm a large safety margin for the compounds of formulas (83), (84), (85) and (86), which substantially improves the therapeutic index in humans, and It may lead to being suitable for intravenous administration at therapeutically effective doses and doses.

5.5 Example 6: Increasing pH Improves Toxicological Profile Three nitroxyl donors (CXL-1020, Compound (2), and Compound (86)) were added to pH 4 and pH 6 (in potassium acetate buffer). ) And evaluated the toxicological profile of these compositions. For pH 4 samples, the composition is mixed with a 1: 1 molar ratio of nitroxyl donor: CAPTISOL®, the mixture is lyophilized, and then the lyophilized mixture is diluted to D5W. It was prepared by. For pH 6 samples, the composition is mixed with a 1: 1 molar ratio of nitroxyl donor: CAPTISOL®, the mixture is lyophilized, and then the lyophilized mixture is mixed with 5 mM potassium phosphate. It was prepared by diluting to D5W containing The compound was injected at an amount of 3 μg / kg / min. As shown in FIG. 4, the toxicology of the three compounds improved as the pH of the injectate increased from approximately 4 to approximately 6.

5.6 Stability evaluation of the concentrate

5.6.1 Example 7: Compound of Formula (1) The stability of the liquid concentrate of the compound of formula (1) and CAPTISOL® was evaluated. Three concentrations of the compound of formula (1) were evaluated: 21.2 mg / mL, 50 mg / mL and 100 mg / mL. Samples were prepared at three target concentrations in four aqueous vehicles containing different ratios of CAPTISOL® as summarized in Table 9. When the appropriate amount of solid and vehicle were mixed and dissolved completely, the pH of each sample was adjusted to 4.0 by adding 1N NaOH. Samples were prepared on a 1.5 mL scale. Aliquots were stored at 2-8 ° C and 25 ° C.

  At the time of preparation and after 1, 3 and 7 days of storage, samples were removed from each temperature condition and their visual appearance was noted. Samples were analyzed by HPLC (XBridge phenyl column (Waters); UV absorbance detector at 272 nm; mobile phase was a step gradient of aqueous acetonitrile containing 0.1% (v / v) formic acid) The pH was measured. The results are summarized in Table 10 and Table 11. The recovered value was normalized to the concentration observed immediately after preparation of the concentrate (t = 0). Complete recovery (within the accuracy of the method) was achieved in all samples stored at 2-8 ° C for 7 days, but not all samples stored at 25 ° C.

  Correspondingly, the drop in pH and the increase in yellow intensity in the refrigerated samples were not as pronounced as the samples stored at a temperature of 25 ° C. Complete recovery was observed after 7 days for 21.2 and 50 mg / mL samples prepared in 30% CAPTISOL® and after 3 days for 100 mg / mL samples prepared in the same vehicle. Over 90% recovery was also observed after 3 days in a 50 mg / mL sample prepared in 20% CAPTISOL®. Stability was highest at lower concentrations, higher ratios of CAPTISOL®, and lower temperatures.

5.6.2. Example 8: Compound of Formula (2) Liquid Concentration of Compound of Formula (2) in Vehicle 30% CAPTISOL® (w / v) at pH 4.0 over 7 days at 4 ° C. and 25 ° C. The storage stability of 30 mg / mL was evaluated at time points after 1, 3 and 7 days. At each time point, visual appearance, pH, and HPLC (XBridge phenyl column (Waters); 272 nm UV absorbance detector; mobile phase of aqueous acetonitrile containing 0.1% (v / v) formic acid. Samples were evaluated for concentration and purity by step gradient).

  Accurately weigh 30 grams of CAPTISOL® into a 150 mL beaker and dissolve in 45 mL of water to bring the selected vehicle, CAPTISOL® (30% w / v), into water adjusted to pH 4.0. Prepared. The pH was adjusted to pH 4.0 by adding 0.1N HCl. Subsequently, the vehicle was transferred to a volumetric flask and made up to a final volume of 100 mL by adding water. After incubating for 30 minutes at a temperature of about 25 ° C., the pH of the vehicle was readjusted to pH 4.0 by adding 0.1 N HCl. The vehicle formed a colorless solution without turbidity.

  A concentrated solution of the compound of formula (2) was prepared as follows. A stir bar and 30 mL of vehicle were added to a 150 mL beaker. Approximately 1.8 g of the compound of formula (2) was dispensed and transferred to a beaker with low to moderate stirring. After stirring for 45 minutes at a temperature of about 25 ° C. (protection from light), the concentrate is a non-turbid colorless solution in which some small white agglomerates of the compound of formula (2) are suspended in the solution. Formed. Residual agglomerates were gently crushed using a spatula. After an additional 45 minutes of stirring, the concentrate formed a colorless solution with no turbidity and no visible solids. The concentrate was then filtered (0.2 μm) through a 0.22 μm PVDF syringe filter.

  For the t = 0 hour test, aliquots are dispensed into vials and HPLC (XBridge phenyl column (Waters); 272 nm UV absorbance detector; mobile phase contains 0.1% (v / v) formic acid. The pH of the sample was determined. A 12-ml portion of 1 mL of the concentrate was dispensed into microcentrifuge tubes for storage at 4 ° C and 25 ° C. Approximately 24, 72, and 168 hours after storage, 2 aliquots were withdrawn from each storage condition and assessed for visual appearance, pH, and concentration and purity by HPLC. All samples were colorless solutions without turbidity. The pH of samples stored at 4 ° C. and 25 ° C. dropped from 3.7 to 3.6 and 3.3, respectively, over 7 days. Both vehicles maintained the compound of formula (2) at a concentration of 30 mg / mL over 7 days as summarized in Table 12. In Table 12, the term “c / c” refers to being turbid and colorless. No detectable levels of known degradation products (compound of formula (101)) were observed.

5.7 Stability of solutions for intravenous administration

5.7.1 Example 9: Compound of Formula (1)-Solution for Administration Stored at 25 ° C Formula (1) of Formula (1) prepared from CAPTISOL® concentrate diluted in a commercial IV excipient The stability of the compound dosing solution was evaluated at 0, 8, 12, 16, 24 and 48 hours analysis points over 48 hours at 25 ° C. after dilution. Two studies were performed with separate sets of dosing solutions for the required analysis points. The first (Group A) included all time points except 16 hours. The second (Group B) involved analysis only at 0 and 16 hours. The concentrates used to prepare the two sets of dosing solutions were two concentrates consisting of the same lot of lyophilized drug product (24 mg / mL of the compound of formula (1) / 30% CAPTISOL®). Prepared from individual vials.

Concentrate Preparation One vial of lyophilized drug product (24 mg / mL compound of formula (1) / 30% CAPTISOL®, pH 4) is reconstituted with 10 mL water for injection quality water (WFI) Each concentrate was prepared (group A and B dosing solution). The pH value of the resulting solution was measured and found to be approximately 3.9 for both vials. No pH adjustment was made. Dilute the concentrate and analyze by HPLC (XBridge phenyl column (Waters); UV absorbance detector at 272 nm; mobile phase step gradient of aqueous acetonitrile containing 0.1% (v / v) formic acid) However, due to the contribution of dissolved API and CAPTISOL® to the total volume of the solution, in both vials the compound of formula (1) was 20-20 mg rather than the nominal value of 24 mg / mL. / ML contained.

Excipient preparation Commercially available potassium acetate and potassium phosphate solutions were selected for evaluation. Potassium acetate was obtained commercially and the US Pharmacopoeia potassium phosphate solution was prepared for the commercial product according to Hospira's product description. Each solution was diluted to 10 mM in 5% dextrose (D5W) and 2.5% dextrose (D2.5W). Commercially available D5W was diluted 2-fold with WFI quality water to produce a D2.5W solution. The pH of each concentrated and diluted solution was measured. These results are shown in Table 13.

Preparation of dosing solution Concentrates of the compound of formula (1) were diluted in volume to a 10 mM excipient solution on a 5 mL scale, and 8, 1, and 0.1 mg / mL as summarized in Table 14. A concentration of the compound of formula (1) was achieved. Each sample was prepared in duplicate. The dextrose content in the 10% CAPTISOL® solution was reduced to ensure that the dosing solution was substantially isotonic. Each solution was stored at 25 ° C.

Sample analysis Samples were analyzed at the time of preparation and after 8, 12, 16, 24 and 48 hours of storage at 25 ° C. Paying attention to the visual appearance of each sample, the pH was measured, and each sample was analyzed by HPLC for the concentration and presence of the main degradation product, compound of formula (100).

Results The results of stability evaluation are shown in Table 15, Table 16, and Table 17. In Table 17, the presence of a peak corresponding to a decomposition product (compound of formula (100)) in the sample is represented by “X”.

  These results were generally consistent between the corresponding dosing solutions prepared in pairs and in Groups A and B for each repeat. Differences in recovery were observed between replicates at 24 and 48 hour time points for samples prepared to contain 0.1 mg / mL of the compound of formula (1) in phosphate.

  Complete recovery (within the accuracy of the HPLC method) and detectable degradation product (within the accuracy of the HPLC method) for samples prepared in acetate and phosphate based excipients with 8 mg / mL of the compound of formula (1) The absence of the compound of formula (100)) peak was maintained over 48 hours. These samples actually contained approximately 7 mg / mL of the compound of formula (1), consistent with the concentration of the compound of formula (1) in the concentrate being 20-21 mg / mL. . In both excipients, stability was better in the sample prepared to 8 mg / mL of the compound of formula (1) than in the sample prepared to a lower concentration. Without being bound by theory, the stability of these samples is superior to those prepared with lower concentrations of the compound of formula (1) than CAPTISOL (registered). (Trademark) (10% in dilute solution).

  All samples remained turbid and colorless over 48 hours of storage. The pH of all samples decreased over time. The known degradation product (compound of formula (100)) is the compound of formula (1) at the time of preparation (at time t0) as well as the compound of formula (1) for all samples prepared to contain 0.1 mg / mL of the compound of formula (1) All samples prepared to contain 0.1 mg / mL and 1 mg / mL were observed at all subsequent time points.

  In general, the stability decreased as the concentration of the compound of formula (1) decreased. Without being bound by theory, the decrease in stability was likely due to the low ratio of CAPTISOL® in the dosing solution. The initial extent of degradation (up to 16 hours) was similar to samples prepared to contain 0.1 mg / mL of the compound of formula (1) in an acetate and phosphate based excipient. However, the stability of the sample prepared to contain 1 mg / mL demonstrated significantly better stability in acetate than in phosphate.

5.7.2 Example 10: Compound of Formula (1)-Stored at -2 ° C to 8 ° C and then stored at 25 ° C Administration solution diluted in commercial IV excipient CAPTISOL® Concentration The stability of the solution for administration of the compound of formula (1) prepared from the product was prepared as described in Example 9. The solution was evaluated at 2-8 ° C for 24 hours and then at 25 ° C for 48 hours. As shown in Table 18, recovery of the compound of formula (1) was generally higher for all dosing solutions than for the corresponding sample stored at 25 ° C. (Table 16 from the previous example). This suggests improved stability in the case of dosage solutions prepared and stored at 2-8 ° C. before being stored at a temperature of 25 ° C. Yes.

5.7.3 Example 11: Compound of Formula (2) —Administration Solution Stored at 25 ° C. A series of administration solutions of the compound of Formula (2) for IV administration was evaluated. Selected concentrates of the compound of formula (2), prepared at 30 mg / mL in 30% CAPTISOL® vehicle at pH 4.0, were prepared at low, medium and high concentrations (0.1, 1 and 0.1 respectively). And 5 mg / mL) diluted into various dosing solutions for evaluation. When the compound of formula (2) is diluted to 0.1 and 1 mg / mL, three dosing solutions, 1) D5W, 2) D5W containing 5 mM K-phosphate (pH = 6), and 3) D5W containing 20 mM K-phosphate (pH = 6) was evaluated. In order to maintain the equimolar osmolarity when the compound of formula (2) was diluted to 5 mg / mL, the concentration of dextrose in the administration solution was reduced to 2.5% (w / v). Therefore, the evaluated solutions for administration were (1) D2.5W, (2) D2.5W containing 5 mM K-phosphate (pH = 6), and (3) 20 mM K-phosphate (pH = 6). ) Including D).

  After storage for approximately 0, 16, 24 and 48 hours at 25 ° C., the potential dosing solution was subjected to visual appearance, pH, osmolality, and HPLC (XBridge phenyl column (Waters); UV absorbance at 272 nm. Detector; mobile phase was evaluated for concentration and purity by aqueous acetonitrile step gradient containing 0.1% (v / v) formic acid. All samples were non-turbid with the sole exception of 5 mg / mL of the compound of formula (2) in D2.5W containing 5 mM phosphate which had a light yellow appearance with no turbidity after 48 hours at 25 ° C. It was a colorless solution. With the sole exception of 1 mg / mL of the compound of formula (2) in D5W with 20 mM phosphate, having an osmolarity of approximately 350 mOsm / kg, all solutions were equimolar (290 ± 50 mOsm / Kg). In addition, with the exception of 5 mg / mL of the compound of formula (2) in D2.5W containing 5 mM phosphate, all other dosing solutions were at target concentrations of 0.1, 1 and 5 mg / mL over 48 hours. The compound of formula (2) was maintained. Furthermore, the compound of formula (101), which is a known degradation product formed from the release of active HNO groups, is observed in a small amount by HPLC after 16 hours at 25 ° C. in an administration solution containing a phosphate buffer. It was done. The observed amount of the compound of formula (101) was about the detection limit of this method.

  The stability of the 5 mg / mL dosing solution of the compound of formula (2) was further evaluated as a function of pH and buffer. A concentrated solution of the compound of formula (2), prepared at 30 mg / mL in 30% CAPTISOL® vehicle at pH 4.0, is diluted to 5 mg / mL to give four potential dosing solutions. did. These four solutions for administration: 1) D2.5W, 5 mM K-phosphate (pH = 6.0), 2) D2.5W containing 5 mM K-citrate (pH = 6.0), 3 ) D2.5W, 5 mM K-citrate (pH = 5.0), and 4) D2.5W, 5 mM K-acetate (pH = 5.0). All administration solutions of the compound of formula (2) had equimolar osmolarity (290 ± 50 mOsm / kg). After storage at 25 ° C. for approximately 24 and 48 hours, the dosing solution was evaluated for visual appearance, pH, and concentration and purity by HPLC. The non-phosphate administration solution was non-turbid and colorless, and the compound of formula (2) was maintained at the target concentration of 5 mg / mL over 48 hours. The administration solution of 5 mg / mL of the compound of formula (2) in D2.5W containing 5 mM phosphate (pH 6.0) was consistent with the selection of the administration solution, but after 48 hours, the formula (2) The compound had a pale yellow appearance with only 60% recovery and no turbidity. Furthermore, the compound of formula (101), which is a known degradation product, is a small amount by HPLC in all samples except 5 mg / mL of the compound of formula (2) in D2.5W, 5 mM citrate (pH 5.0). Observed.

  Even after storage at 25 ° C. for 7 days, the non-phosphate administration solution remained colorless and colorless in appearance. The smallest improvement in acidity over 7 days is measured with 5 mg / mL of the compound of formula (2) in the administration solution of D2.5W, 5 mM citrate, pH 6.0, while pH 5.0 The D2.5W, 5 mM citrate solution for administration had the least pH change over the first 24-48 hours. In addition, after 14 days storage at 25 ° C., the sample containing the pH 6.0 dosing solution containing 5 mM citrate is still a non-turbid colorless solution, while either 5 mM citrate or 5 mM acetate. The solution for administration containing either of them and having a pH of 5.0 was a non-turbid yellow solution. The results are summarized in Table 19.

5.8 Example 12: Evaluation of CAPTISOL® / nitroxyl donor ratio The compound of formula (1) was selected as the nitroxyl donor model. Stability assessment is a concentrate solution containing the molar ratio of CAPTISOL® (MW 2163 g / mol) to the compound of formula (1) (MW 177.18 g / mol) selected based on planned toxicology studies It carried out in. The concentrates evaluated are summarized in Table 20. Concentrate samples were prepared by mixing appropriate amounts of solid and vehicle, and once completely dissolved, the pH of each sample was adjusted to 4.0 by adding 1N NaOH. Samples were prepared on a 1.8 mL scale. Aliquots of each solution were stored at 25 ° C.

  Each concentrate solution was further diluted in IV excipients to the highest and lowest concentrations expected to be administered during toxicology studies (respectively the compound of formula (1) 8 mg / mL and 0.02 mg / mL). The evaluated dosing solutions are summarized in Table 21. The vehicle was selected to produce an administrable formulation that is nearly isotonic with human blood (about 290 mOsm / kg water). Dilution was performed on a 5 mL scale for high concentration samples and a 25 mL scale for low concentration samples. Aliquots of each solution were stored at 25 ° C.

  Samples were removed from storage at the time of preparation (t0) and 1 day (24 hours) and 2 days (48 hours) of storage, and their visual appearance was noted. All concentrate samples remained light yellow with no turbidity over 48 hours. The administration solutions D7 to D9 were very light in color with no turbidity at each time point, and the administration solutions D10 to D12 were not turbid and remained colorless. At each time point, analyze the sample by HPLC (XBridge phenyl column (Waters); UV absorbance detector at 272 nm; mobile phase is a step gradient of aqueous acetonitrile containing 0.1% (v / v) formic acid) did. The results of HPLC analysis of the concentrate are summarized in Table 22. The results of HPLC analysis of the dosing solution are summarized in Table 23. Complete recovery (within the accuracy of the method) was achieved in all concentrates and dosing solutions over a 48 hour period. The major degradation products of the compound of formula (1) (ie the compound of formula (100)) were observed at low concentrations in the dosing solution prepared to 0.02 mg / mL. The degradation product concentration did not increase over time and did not affect the recovery of the compound of formula (1).

5.9 Synthesis of Compounds The compounds disclosed herein can be made according to the methods disclosed below or by procedures known in the art. Starting materials for the reaction can be commercially available or can be prepared by known procedures or obvious modifications thereof. For example, some of the starting materials are available from commercial sources such as Sigma-Aldrich (St. Louis, MO). Others can be prepared by procedures disclosed in standard reference books, such as March's Advanced Organic Chemistry (John Wiley and Sons) and Larock's Comprehensive Organic Transformations (VCH Publishers), or obvious modifications thereof.

Preparation of N-hydroxy-5-methylfuran-2-sulfonamide (1) A solution of hydroxylamine (0.92 mL of 50% aqueous solution, 13.8 mmol) in THF (6 mL) and water (2 mL) cooled to 0 ° C. To was added 5-methylfuran-2-sulfonyl chloride (1 g, 5.5 mmol) dropwise as a solution in THF (6 mL) to maintain the temperature below 10 ° C. The reaction was stirred for 5 minutes, after which time TLC (1: 1 hexane: ethyl acetate (H: EA)) showed substantially complete consumption of the sulfonyl chloride. The reaction was diluted twice with 50 mL dichloromethane (DCM) and the organic portion was separated and washed with water (10 mL). The organic portion was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was chromatographed on a silica gel column eluted with heptane: EtOAc, then triturated with heptane to give the title compound as a yellow solid (0.59 g, 61% yield). LC-MS t _R = 0.91 min; ¹ H NMR (DMSO, 500 MHz) δ ppm 9.82 (1H, d, J = 3.1 Hz), 9.64 (1H, d, J = 3.2 Hz), 7.10 (1H, d , J = 3.4Hz), 6.36 (1H, d, J = 3.4Hz), 2.36 (3H, s).

Preparation of N-Hydroxy-3-methanesulfonylbenzene-1-sulfonamide (2) 3-Methanesulfonylbenzene-1-sulfonyl chloride The intermediate 3-methanesulfonylbenzene-1-sulfonyl chloride is prepared according to Park et al., Synthesized according to the method disclosed in J. Med. Chem. 51 (21): 6902-6915 (2008). Specifically, methylsulfonylbenzene (110 g, 0.7 mol) was heated in chlorosulfonic acid (450 mL, 6.7 mol) at 90 ° C. for 18 hours, after which the reaction mixture was cooled to a temperature of about 21 ° C. Slowly poured onto crushed ice. The resulting slurry was extracted twice into EtOAc (2 L for each extraction). The combined organic portions were washed with brine (50 mL), then dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the intermediate sulfonyl chloride as an off-white solid (125 g, 75% yield). It was. ¹ H NMR (400 MHz, CDCl ₃ ) δppm 8.61 (1 h, t, J = 1.7Hz), 8.35-8.31 (2H, m), 7.90 (1H, t, J = 7.9Hz), 3.15 (3H, s ).

N-hydroxy-3-methanesulfonylbenzene-1-sulfonamide—To a solution of aqueous hydroxylamine (50% aqueous solution 16 mL, 245 mmol) in THF (150 mL) and water (25 mL) cooled to −5 ° C., the reaction temperature was 10 3-Methanesulfonylbenzene-1-sulfonyl chloride (25 g, 98 mmol) was added slowly while maintaining below <RTIgt; The reaction is maintained at this temperature until substantially complete consumption of the sulfonyl chloride is observed (about 5 minutes), after which the reaction is diluted with DCM (250 mL) and the organic portion is separated, Washed twice with 50 mL of water. The aqueous extracts were combined and rewashed twice with DCM (250 mL for each wash). All organic portions were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a beige solid. Trituration with heptane: EtOAc (1: 1; v: v) gave the title compound as a beige solid (14 g, 56% yield). _LC-MS t R = 0.90 min; high resolution mass spectrometry (HRMS): Theoretical value _{(C 7 H 9 NO 5 S} 2) = 249.9844, measured ^{= 249.9833; 1 H NMR (500} MHz, DMSO-d ₆ ) δppm 9.85 (2H, q, J = 3.3Hz), 8.31 (1H, t, J = 1.6Hz), 8.28 (1H, dt, J = 7.8, 1.3Hz), 8.14-8.19 (1H, m), 7.93 (1H, t, J = 7.9Hz), 3.32 (3H, s).

Preparation of N-hydroxy-5-methyl-1,2-oxazole-4-sulfonamide (3) Hydroxylamine (0.45 mL of 50% aqueous solution, 13) in THF (6 mL) and water (1 mL) cooled to 0 ° C. .7 mmol), 5-methyl-1,2-oxazole-4-sulfonyl chloride (1.0 g, 5.5 mmol) was added in portions, keeping the temperature below 10 ° C. The reaction was stirred for 10 minutes, after which LC-MS showed complete consumption of the sulfonyl chloride. The reaction was diluted with DCM (50 mL) and the organic portion was separated and washed with water (10 mL). The organic portion was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was triturated with diethyl ether to give the title compound as an off-white solid (0.45 g, 46% yield). _LC-MS t R = 0.66 min; HRMS: theory _{(C 4 H 6 N 2 O} 4 S) = 176.997, measured value ^{= 176.9972; 1 H NMR (500} MHz, DMSO-d 6) δppm 9.83 (1H, s), 9.68 (1H, br.s.), 8.77 (1H, s), 2.64 (3H, s).

Preparation of N-hydroxy-1-benzofuran-7-sulfonamide (4) To a solution of hydroxylamine (50% aqueous solution 0.76 mL, 11.5 mmol) in THF (12 mL) and water (2 mL) cooled to 0 ° C. 1-benzofuran-7-sulfonyl chloride (1 g, 4.6 mmol) was added in portions and the temperature was maintained below 10 ° C. The reaction was stirred for 10 minutes, after which time TLC (heptane: EtOAc) showed substantially complete consumption of the sulfonyl chloride. The reaction was diluted with DCM (25 mL) and the organic portion was separated and washed with water (10 mL). The organic portion was dried over sodium sulfate, filtered and concentrated under reduced pressure. Trituration with heptane gave the title compound as an off-white solid (0.63 g, 64% yield). LC-MS t _R = 1.32; ¹ H NMR (500 MHz, DMSO) δ 9.75 (d, J = 3.0Hz, 1H), 9.66 (1H, d, J = 3.1Hz), 8.18 (1H, d , J = 2.2Hz), 8.01 (1H, d, J = 6.8Hz), 7.72 (1H, d, J = 7.7Hz), 7.45 (1H, t, J = 7.7Hz), 7.14 (1H, d, J = 2.2Hz).

Preparation of 4- (hydroxysulfamoyl) -N- (propan-2-yl) thiophene-2-carboxamide (5) N- (propan-2-yl) thiophene-2-carboxamide DCM with stirring under nitrogen A solution of propan-2-amine (9.7 mL, 112.6 mmol) in (150 mL) was cooled at 0 ° C. Thiophene-2-carbonyl chloride (11.0 mL, 102.3 mmol) was added dropwise, followed by ethyldiisopropylamine (19.5 mL, 112.6 mmol). The reaction mixture was warmed to a temperature of about 21 ° C. and stirring was continued for 18 hours, after which the reaction mixture was further diluted with DCM (100 mL) to give 1M HCl solution (2 × 50 mL), water (1 × 50 mL), Wash with saturated NaHCO ₃ solution (1 × 25 mL), and brine (2 × 25 mL), then dry the organic layer over magnesium sulfate, filter, and concentrate under reduced pressure to give N- (propan-2-yl). Thiophene-2-carboxamide was obtained as a white solid (18.1 g, 99.2% yield). LC-MS t _R = 1.43 min; ¹ H NMR (500 MHz, chloroform-d) δ ppm 7.54-7.46 (1H, m), 7.43 (1H, d, J = 5.0 Hz), 7.04 (1H, t, J = 4.3Hz), 6.00 (1H, br s), 4.31-4.16 (1H, m, J = 6.6Hz), 1.24 (6H, d, J = 6.7Hz).

N- (propan-2-yl) thiophene-2-carboxamide (17.3 g) in 5-[(propan-2-yl) carbamoyl] thiophene-3-sulfonyl chloride chlorosulfonic acid (68.1 mL, 1023.2 mmol) , 102.3 mmol) was heated at 100 ° C. for 2 hours, after which the solution was cooled to a temperature of about 21 ° C. and poured carefully onto ice (500 mL). This aqueous solution was extracted into DCM (2 × 250 mL) and the combined organic portions were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the desired compound as 5-[(propan-2-yl) carbamoyl] thiophene. Obtained as a mixture with 2-sulfonyl chloride, which was separated by silica gel column eluted with heptane: EtOAc to give the product as a white solid (9.9 g, 36.1% yield). LC-MS t _R = 1.85 min; ¹ H NMR (250 MHz, chloroform-d) δ ppm 8.33 (1H, d, J = 1.4 Hz), 7.82 (1H, d, J = 1.4 Hz), 6.24 (1H , d, J = 6.5Hz), 4.27 (1H, qd, J = 6.6, 14.4Hz), 1.30 (6H, d, J = 6.7Hz).

4- (Hydroxysulfamoyl) -N- (propan-2-yl) thiophene-2-carboxamide Hydroxylamine (50% aqueous solution 6.1 mL, 95) in THF (30 mL) and water (10 mL) cooled to 0 ° C. .3 mmol) in a solution of 5-[(propan-2-yl) carbamoyl] thiophene-3-sulfonyl chloride (9.9 g, 36.9 mmol) in THF (30 mL) at a temperature below 10 ° C. Added dropwise to maintain. The reaction was stirred for 10 minutes, after which LC-MS showed complete consumption of the sulfonyl chloride. The reaction was diluted with DCM (100 mL) and the organic portion was separated and washed with water (50 mL). The aqueous layer was re-extracted with DCM (2 × 50 mL) and EtOAc (50 mL). All organic portions were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. Trituration with heptane: EtOAc gave the title compound as a white solid (6.4 g, 65.4% yield). LC-MS t _R = 1.22 min; HRMS: Theoretical (C ₈ H ₁₂ N ₂ O ₄ S ₂ ) = 263.0160, Found = 263.0164; ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.69 (1H, d, J = 3.2Hz), 9.59 (1H, d, J = 3.2Hz), 8.61 (1H, d, J = 7.6Hz), 8.34 (1H, d, J = 1.4Hz), 8.10 (1H, d, J = 1.1Hz), 3.92-4.16 (1H, m), 1.15 (6H, d, J = 6.6Hz).

Preparation of N-hydroxy-1-benzofuran-3-sulfonamide (6) 1-benzofuran-3-sulfonyl chloride 1-benzofuran-3-sulfonyl chloride was prepared according to Park et al., Bioorg. Med. Chem. Letters 18 (14 ): 3844-3847 (2008). To a solution of sulfuryl chloride (4.9 mL, 60.4 mmol) in DMF (13 mL) was added benzofuran (4.2 g, 35.6 mmol) at 0 ° C. and the reaction was heated to 85 ° C. for 3 hours. After the reaction was substantially complete as determined by TLC (heptane: EtOAc), the reaction was cooled to a temperature of about 21 ° C. and poured onto ice. The product was extracted into EtOAc (2 × 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was chromatographed on a silica gel column eluted with heptane: EtOAc to give the sulfonyl chloride as a yellow oil (0.27 g, 3.5% yield). LC-MS t _R = 2.06 min; ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 7.93 (1H, s), 7.68-7.81 (1H, m), 7.54 (1H, dd, J = 8.1, 0.9Hz), 7.17-7.38 (2H, m).

N-hydroxy-1-benzofuran-3-sulfonamide To a solution of hydroxylamine (50% aqueous solution 0.1 mL, 3.0 mmol) in THF (1.25 mL) and water (0.25 mL) cooled to 0 ° C. was added. 1-Benzofuran-3-sulfonyl chloride (0.26 g, 1.2 mmol) was added in small portions, keeping the temperature below 10 ° C. The reaction was stirred for 10 minutes, after which LC-MS showed complete consumption of the sulfonyl chloride. The reaction was diluted with DCM (10 mL) and the organic portion was separated and washed with water (5 mL). The organic portion was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was chromatographed on a silica gel column eluted with heptane: EtOAc, then triturated with heptane: DCM to give the title compound as a yellow solid (0.03 g, 12% yield). LC-MS t _R = 1.45; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.75 (2H, s), 8.68 (1H, s), 7.86 (1H, d, J = 7.7 Hz), 7.76 (1H, d, J = 8.2Hz), 7.36-7.57 (2H, m).

Preparation of N-hydroxy-5-methyl-2- (trifluoromethyl) furan-3-sulfonamide (7) Hydroxylamine (50% aqueous solution 0. 0%) in THF (6 mL) and water (1 mL) cooled to 0 ° C. 66 mL, 10.1 mmol) in a solution of 5-methyl-2- (trifluoromethyl) furan-3-sulfonyl chloride (1 g, 4.0 mmol), keeping the temperature below 10 ° C. added. The reaction was stirred for 5 minutes, after which LC-MS showed complete consumption of the sulfonyl chloride. The reaction was diluted with DCM (25 mL) and the organic portion was separated and washed with water (10 mL). The organic portion was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was triturated with heptane to give the title compound as an off-white solid (0.7 g, 71% yield). LC-MS t _R = 1.64 min; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.81 (1H, d, J = 3.3 Hz), 9.68 (1H, d, J = 3.2 Hz), 7.37 ( 1H, s), 2.60 (3H, s).

Preparation of N-hydroxy-5-methanesulfonylthiophene-3-sulfonamide (8) 5-Methanesulfonylthiophene-3-sulfonyl chloride and 5-methanesulfonylthiophene-2-sulfonyl chloride chlorosulfonic acid (2.9 mL, 43. A solution of 2-methanesulfonylthiophene (1.0 g, 6.2 mmol) in 2 mmol) is heated at 90 ° C. for 1 hour, after which the solution is cooled to a temperature of about 21 ° C. and carefully poured onto ice (20 mL). I put it in. This aqueous solution was extracted into DCM (2 × 25 mL). The organic portions were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the sulfonyl chloride as a mixture with 5-methanesulfonylthiophene-2-sulfonyl chloride. When this mixture was chromatographed on a silica gel column eluted with heptane: EtOAc, only a portion was separated into two isomers and the sulfonyl chloride was carried over to the next step (85: with other isomers: 15 mixture as 0.5 g, 31% yield). LC-MS t _R = 1.67 min; ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 7.99 (1H, d, J = 1.6 Hz), 7.69 (1H, d, J = 1.6 Hz), 3.36 ( 3H, s).

N-hydroxy-5-methanesulfonylthiophene-3-sulfonamide To a solution of hydroxylamine (50% aqueous solution 0.3 mL, 4.8 mmol) in THF (6 mL) and water (1 mL) cooled to 0 ° C. was added 5- A mixture of methanesulfonylthiophene-3-sulfonyl chloride and 5-methanesulfonylthiophene-2-sulfonyl chloride (85:15 by LC-MS) (0.5 g, 1.9 mmol) was aliquoted to bring the temperature below 10 ° C. Added to maintain. The reaction was stirred for 5 minutes, after which LC-MS showed complete consumption of the sulfonyl chloride. The reaction was diluted with DCM (10 mL) and the organic portion was separated and washed with water (5 mL). The organic portion was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was chromatographed by neutral preparative reverse phase HPLC to give the title compound as a white solid (0.07 g, 14% yield). LC-MS t _R = 0.94; ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.85 (1H, d, J = 2.8 Hz), 9.78 (1H, d, J = 2.8 Hz), 8.65 (1H , d, J = 1.6Hz), 7.98 (1H, d, J = 1.4Hz), 3.46 (3H, s).

1-acetyl-5-bromo-N-hydroxy-2,3-dihydro-1H-indole-6-sulfonamide (9)
1- (5-Bromo-2,3-dihydro-1H-indol-1-yl) ethane-1-one 5-Bromo-2,3-dihydro-1H-indole in acetic acid (12 mL) (1.5 g, To a solution of 7.5 mmol) acetyl chloride (3.57 g, 45.4 mmol) was added. The reaction was heated to 90 ° C. until the consumption of starting material was substantially complete (about 1 hour) and the solvent was removed under reduced pressure. The organic portion was diluted in ethyl acetate and washed with sodium bicarbonate solution. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a brown solid (1.76 g, 99.99% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 7.96 (1H, d, 8.7Hz), 7.40 (1H, d, 0.8Hz), 7.30 (1H, dd, 8.5, 2.0Hz), 4.09 (2H, t , 8.6Hz), 3.14 (2H, t, 8.5Hz), 2.14 (3H, s).

1-acetyl-5-bromo-2,3-dihydro-1H-indole-6-sulfonyl chloride 1- (5-bromo-2,3-dihydro-1H-indol-1-yl) ethane-1-one (1 0.2 g, 5.0 mmol) and chlorosulfonic acid (3.5 g, 30 mmol) were heated to 80 ° C. for 18 hours in a sealed tube. The reaction is quenched by pouring onto ice and the resulting solid is filtered and dried under reduced pressure and then chromatographed on a silica gel column eluted with 40% heptane: ethyl acetate to turn off the title compound. Obtained as a white solid (0.95 g, 56% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 8.60 (1H, s), 7.37 (1H, s), 4.09 (2H, t, 8.6Hz), 3.11 (2H, t, 8.5Hz), 2.14 (3H , s).

1-acetyl-5-bromo-N-hydroxy-2,3-dihydro-1H-indole-6-sulfonamide-aqueous hydroxylamine (1) in THF (2.5 mL) and water (0.5 mL) at -10 <0> C. 1-acetyl-5-bromo-2,3-dihydro-1H-indole-6-sulfonyl chloride (0.5 g, 1.48 mmol) was subdivided into a solution of .6 mL, 3.7 mmol, 50% aqueous). Was added while maintaining the internal temperature at -5 ° C. Stirring was continued at low temperature until complete consumption of the sulfonyl chloride was observed by LC-MS. Diethyl ether was added and the reaction was washed with 10% citric acid solution. The organics were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-acetyl-5-bromo-N-hydroxy-2,3-dihydro-1H-indole-6-sulfonamide as an off-white solid. (0.32 g, 66% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 9.44-9.76 (2H, m), 8.72 (1H, s), 7.68 (1H, s), 4.16 (2H, t, 8.6Hz), 3.22 (2H, t, 8.8 Hz), 2.17 (3H, s); predicted value [M−H] ⁻ = 332.9545; observed value [M−H] ⁻ = 332.9553.

2-Chloro-N-hydroxy-5- (hydroxymethyl) benzene-1-sulfonamide (10)
2-Chloro-5- (hydroxymethyl) aniline To a solution of 1-chloro-4- (hydroxymethyl) -2-nitrobenzene (4.5 g, 24 mmol) in EtOH (23 mL) and water (4.5 mL) was added iron. (3.45 g, 84 mmol) and HCl (9 drops) were added. The reaction was heated to 85 ° C. for 4 hours. The cooled reaction mixture was filtered through celite, washed with EtOAc, concentrated under reduced pressure and used directly in the next step (3.5 g, 95% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δ7.09 (1H, d, 8.1Hz), 6.76 (1H, d, 2.0Hz), 6.47 (1H, dd, 8.1, 1.9Hz), 5.10 (1H, t, 5.7Hz), 4.34 (2H, d, 5.8Hz).

2-Chloro-5- (hydroxymethyl) benzene-1-sulfonyl chloride 2-Chloro-5- (hydroxymethyl) aniline (0. 2) in acetic acid (3.2 mL) and HCl (0.8 mL) cooled to 0 ° C. To a solution of 5 g, 3.1 mmol) sodium nitrite (0.24 g, 3.5 mmol) was added in small portions while maintaining the internal temperature <5 ° C. The reaction mixture was stirred for 1 hour at 0 ° C. At the same time, CuCl ₂ .H ₂ O (0.5 g, 3.1 mmol) was suspended in AcOH: water (3.2 mL: 1.6 mL) at 0 ° C. until 0 ° C. until all the CuCl ₂ was dissolved. Stir with. The SO ₂ gas was condensed into the flask at −78 ° C. by using a cold finger, the diazo compound and the CuCl ₂ solution were added, and the reaction was warmed to 0 ° C. The reaction was warmed to a temperature of about 25 ° C. over 2 hours. The reaction was quenched by adding to ice and extracted into DCM (2 × 10 mL). The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow oil. The sulfonyl chloride was chromatographed on a silica gel column eluted with DCM to give the sulfonyl chloride as a yellow oil (0.2 g, 26% yield). ¹ H NMR (250 MHz, chloroform-d) δ8.14 (1H, d, 1.2Hz), 7.41-7.83 (2H, m), 4.79 (2H, s).

2-Chloro-N-hydroxy-5- (hydroxymethyl) benzene-1-sulfonamide Hydroxylamine (0.45 mL of 50% aqueous solution, 15.5 mmol) in tetrahydrofuran (5 mL) and water (1 mL) cooled to −5 ° C. ) In a solution of 2-chloro-5- (hydroxymethyl) benzene-1-sulfonyl chloride (1.25 g, 5.1 mmol) in tetrahydrofuran (2.5 mL), keeping the temperature below 0 ° C. Added dropwise. The reaction was stirred until TLC showed substantially complete consumption of starting material (approximately 30 minutes). The reaction was diluted with dichloromethane (50 mL) and the organic portion was washed with water (1 mL) then separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. Trituration with n-pentane gave N-hydroxy-5-methylfuran-2-sulfonamide as an off-white solid (0.37 g, 30% yield). ¹ H NMR (300 MHz, DMSO) δ9.74 (2H, q, 3.0Hz), 7.98 (1H, d, 1.4Hz), 7.60 (2H, dt, 8.2, 5.0Hz), 5.51 (1H, s), 4.57 (2H, s).

1-acetyl-5-chloro-N-hydroxy-2,3-dihydro-1H-indole-6-sulfonamide (11)
1- (5-Chloro-2,3-dihydro-1H-indol-1-yl) ethan-1-one 5-chloro-2,3-dihydro-1H-indole in acetic acid (60 mL) (6.0 g, Acetyl chloride (18.4 g, 23 mmol) was added to the 39 mmol) solution. The reaction was heated to 80 ° C. until the consumption of starting material was substantially complete (about 1 hour) and the solvent was removed under reduced pressure. The organic portion was diluted in ethyl acetate (200 mL) and washed with sodium bicarbonate solution (2 × 100 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1- (5-chloro-2,3-dihydro-1H-indol-1-yl) ethan-1-one as a brown solid (7 0.1 g, 93% yield). ¹ H NMR (400 MHz, DMSO) δ8.00 (1H, d, 8.6Hz), 7.28 (1H, s), 7.18 (12H, dd, 8.6, 2.0Hz), 4.10 (2H, t, 8.6Hz), 3.13 (2H, t, 8.6Hz), 2.14 (3H, s).

1-acetyl-5-chloro-2,3-dihydro-1H-indole-6-sulfonyl chloride 1- (5-chloro-2,3-dihydro-1H-indol-1-yl) ethane-1-one (7 g 36 mmol) and chlorosulfonic acid (16.68 g, 143 mmol) were heated to 70 ° C. for 18 hours. The reaction was quenched by adding to ice and the resulting solid was extracted into ethyl acetate (250 mL). The resulting solution was washed with water (2 × 100 mL), the organic portion was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give acetyl-5-chloro-2,3-dihydro-1H-indole-6. -Sulfonyl chloride was obtained. The product is chromatographed on a silica gel column eluted with 40-50% ethyl acetate: hexanes to give off-white color of 1-acetyl-5-chloro-2,3-dihydro-1H-indole-6-sulfonyl chloride. Obtained as a solid (7.2 g, 68.4% yield). ¹ H NMR (400 MHz, DMSO) δ8.56 (1H, s), 7.19 (1H, s), 4.09 (2H, t, 8.6Hz), 3.10 (2H, t, 8.5Hz), 2.14 (3H, s ).

1-acetyl-5-chloro-N-hydroxy-2,3-dihydro-1H-indole-6-sulfonamide Hydroxylamine (50% aqueous solution 1) in tetrahydrofuran (40 mL) and water (5 mL) cooled to -5 ° C. Solution of 1-acetyl-5-chloro-2,3-dihydro-1H-indole-6-sulfonyl chloride (4.0 g, 13.6 mmol) in tetrahydrofuran (10 mL). As the temperature was added dropwise to maintain the temperature below 0 ° C. The reaction was stirred for 30 minutes and TLC showed substantially complete consumption of starting material. The reaction was diluted with water (5 mL) and the resulting solid was collected under vacuum, further washed with water (2 × 10 mL) and then dried under vacuum to give 1-acetyl-5-chloro-N—. Hydroxy-2,3-dihydro-1H-indole-6-sulfonamide was obtained as a white solid (3.0 g, 76% yield). ¹ H NMR (400 MHz, DMSO) δ9.65 (1H, s), 9.55 (1H, s), 8.72 (1H, s), 7.68 (1H, s), 4.15 (2H, t, 8.6Hz), 3.22 (2H, t, 8.5 Hz), 2.17 (3H, s); predicted value [M−H] ⁻ = 289.005; observed value [M−H] ⁻ = 289.0059.

4,5-dichloro-N-hydroxythiophene-2-sulfonamide (12)
To a solution of hydroxylamine (50% aqueous solution 0.655 mL, 10.0 mmol) in tetrahydrofuran (6 mL) and water (1 mL) cooled to −5 ° C. was added 4,5-dichlorothiophene-2-sulfonyl chloride (1.0 g). 4.0 mmol) as a solution in tetrahydrofuran (1 mL) was added dropwise so as to maintain the temperature below 0 ° C. The reaction was stirred until TLC showed substantially complete consumption of starting material (approximately 10 minutes). The reaction was diluted with diethyl ether (20 mL) and the organic portion was washed with citric acid solution (2 × 1 mL) then separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. Trituration with diethyl ether: heptane gave 4,5-dichloro-N-hydroxythiophene-2-sulfonamide as a white solid (0.35 g, 38% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δ 10.06 (1H, d 2.9 Hz), 10.00 (1H, d, 2.7 Hz), 7.73 (1H, s); predicted value [M−H] ⁻ = 245 Observed value [M−H] ⁻ = 2455.8845.

N-hydroxy-6-methoxy-1-benzofuran-2-sulfonamide (13)
2- (2-Formyl-5-methoxyphenoxy) acetic acid To a mixture of 2-hydroxy-4-methoxybenzaldehyde (10 g, 65 mmol), chloroacetic acid (6.2 g, 65 mmol) and water (80 mL) was added sodium hydroxide (20 mL 5.2 g, 131 mmol) aqueous solution was added. The mixture was stirred slowly and then heated at reflux for 16 hours, after which the reaction mixture was cooled to a temperature of about 25 ° C., at which point the reaction mixture was acidified with concentrated HCl to pH 3. The resulting acidic solution was extracted into ethyl acetate (3 × 50 mL), then dried over sodium sulfate and concentrated under reduced pressure to give the desired compound as a brown oil that was used directly in the next step. (11.5 g, 83% yield). _LC-MS t R = 0.75 ^{min, [M + H] + =} 211.29

6-Methoxy-1-benzofuran To a mixture of 2- (2-formyl-5-methoxyphenoxy) acetic acid (11.4 g, 54 mmol) in acetic anhydride (75 mL) and acetic acid (75 mL) was added sodium acetate (21.0 g, 254 mmol). ) And the reaction was heated to 140 ° C. for 18 hours. After cooling the reaction mixture at a temperature of about 25 ° C., water (100 mL) was added and the resulting aqueous solution was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated sodium bicarbonate solution (3 × 30 mL), dried over sodium sulfate and concentrated under reduced pressure to give the compound as a brown oil. The oil was chromatographed on a silica gel column eluted with 0.5% ethyl acetate in hexanes to give a pale yellow oil (1.6 g, 20%) which was confirmed by ¹ H NMR. . ¹ H NMR (400 MHz, CDCl ₃ ) δ7.53 (1H, t, 3.3Hz) 7.45 (1H, d, 8.5Hz), 7.04 (1H, d, 2.0Hz), 6.88 (1H, dd, 8.5, 2.3 Hz), 6.70 (1H, dd, 2.2, 0.9Hz), 3.86 (3H, s).

6-Methoxy-1-benzofuran-2-sulfonyl chloride To a solution of 6-methoxy-1-benzofuran (1.6 g, 10.8 mmol) in THF (20 mL) at -78 ° C. was added n-BuLi (2. 5M solution, 4.8 mL, 11.8 mmol) was added dropwise and stirring was continued at this temperature for 1 hour. While maintaining the temperature at -50 ° C, sulfur dioxide gas was bubbled into the reaction mixture for 1 hour and stirring was continued at this temperature for an additional hour. To this solution was added N-chlorosuccinamide (2.2 g, 16 mmol) and the reaction mixture was warmed from −20 ° C. to a temperature of about 25 ° C. over 18 hours. The reaction mixture was quenched with water (25 mL) and the organics were extracted into ethyl acetate (2 × 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The sulfonyl chloride was chromatographed on a silica gel column eluted with 2% ethyl acetate in hexanes to give a green solid (0.8 g, 30% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ7.61 (1H, d, 8.8Hz), 7.59 (1H, d, 0.9Hz), 7.09 (1H, d, 2.1Hz), 7.05 (1H, dd, 8.8, 2.2Hz), 3.91 (s, 3H).

N-hydroxy-6-methoxy-1-benzofuran-2-sulfonamide A solution of aqueous hydroxylamine (50% solution 1.6 mL, 33.0 mmol) in THF (18 mL) was added to 6-methoxy in THF (6 mL). A -1-benzofuran-2-sulfonyl chloride solution (2.3 g, 9.3 mmol) was added dropwise at 0 ° C. The reaction was stirred for 30 minutes and TLC showed substantially complete consumption of starting material. The reaction mixture is diluted with diethyl ether (50 mL), washed with water (2 × 15 mL), dried over sodium sulfate and concentrated under reduced pressure to give the compound, which is used using 5% DCM pentane. When powdered, the desired product was obtained as an off-white solid (0.9 g, 40% yield). ¹ H NMR (400 MHz, DMSO) δ 10.13 (1H, d, 2.2Hz), 9.80 (1H, d, 1.9Hz), 7.69 (1H, d, 8.7Hz), 7.63 (1H, d, 0.9Hz) , 7.32 (1H, d, 2.0Hz), 7.03 (1H, dd, 8.7, 2.2Hz), 3.85 (3H, s).

2-Fluoro-N-hydroxy-4-methylbenzene-1-sulfonamide (14)
To a solution of hydroxylamine (50% aqueous solution 1.5 mL, 23.9 mmol) in tetrahydrofuran (12 mL) and water (2 mL) cooled to −10 ° C. was added 2-fluoro-4-methylbenzene-1-sulfonyl chloride (2 0.0 g, 9.6 mmol) was added in small portions, keeping the temperature below 0 ° C. The reaction was stirred for 5 minutes, after which LC-MS showed complete consumption of starting material. The reaction was diluted with diethyl ether (30 mL) and the organic portion was washed with 10% citric acid solution (10 mL) then separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Trituration with heptane: diethyl ether gave N-hydroxy-sulfonamide as an off-white solid (1.06 g, 58% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ9.67 (2H, s), 7.69 (1H, t, 7.8Hz), 7.29 (1H, d, 11.5Hz), 7.23 (1H, d, 8.0Hz) , 2.40 (3H, s); predicted value [M−H] ⁻ = 204.0131; observed value [M−H] ⁻ = 204.0175.

N-hydroxy-2,1,3-benzothiadiazole-5-sulfonamide (15)
To a solution of aqueous hydroxylamine (50% solution 0.7 mL, 10.65 mmol) in tetrahydrofuran (6 mL) and water (1 mL) cooled to −5 ° C. while maintaining the reaction temperature below 10 ° C., 2,1 , 3-Benzothiadiazole-5-sulfonyl chloride (1.0 g, 4.3 mmol) was added slowly. The reaction is maintained at this temperature until complete consumption of the sulfonyl chloride is observed by LC-MS (about 5 minutes), after which the reaction is diluted with ethyl acetate (20 mL) and the organic portion is separated. Wash with water (2 × 5 mL), dehydrate with sodium sulfate, filter, and concentrate under reduced pressure to give N-hydroxysulfonamide as an orange solid that is further washed with sodium bicarbonate solution (10 mL). Thus, it was necessary to remove sulfinic acid impurities. Trituration with heptane: DCM (9: 1, v: v) gave the title compound as an orange solid (0.53 g, 54% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ9.94 (1H, d, 3.2Hz), 9.84 (1H, d, 3.2Hz), 8.62-8.53 (1H, m), 8.42-8.32 (1H, m ), 8.04 (1H, dd, 9.2, 1.7Hz).

N-hydroxy-4-methanesulfonylthiophene-2-sulfonamide (16)
3- (Methylsulfanyl) thiophene—To a solution of 3-bromothiophene (3.3 g, 0.02 mol) in heptane (30 mL) at −40 ° C. was added n-butyllithium (2.5 M solution in hexane, 8.5 mL). ) Was added dropwise. Tetrahydrofuran (3 mL) was added to the flask and 3-lithiothiophene precipitated as a white solid and the reaction mixture was warmed to a temperature of about 25 ° C. To the resulting solution, methyl disulfide (1.97 mL, 0.02 mol) was added dropwise and the reaction mixture was stirred at a temperature of about 25 ° C. for 1 hour. Water (10 mL) was added to the flask, the organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3- (methylsulfanyl) thiophene as a colorless oil (2.6 g, 98% yield). ) Was obtained. ¹ H NMR (500 MHz, chloroform-d) δppm 7.34 (1H, dd, J = 5.0, 3.0Hz), 7.01 (1H, dd, J = 5.0, 1.3Hz), 6.99 (1H, dd, J = 3.0, 1.3Hz), 2.49 (3H, s).

3-Methanesulfonylthiophene To a solution of 3- (methylsulfanyl) thiophene (2.6 g, 19.96 mmol) in acetic acid (20 mL) was added hydrogen peroxide (4.53 mL of 30% aqueous solution, 39.93 mmol). The reaction was heated to reflux for 3 hours, cooled to a temperature of about 25 ° C. for 18 hours, and then acetic acid was removed under reduced pressure. The obtained organic substance was dissolved in ethyl acetate (30 mL), and the whole was washed with a saturated sodium hydrogen carbonate solution (2 × 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil that solidified upon standing and was used directly in the next step (2.2 g, 67.9% yield). ¹ H NMR (500 MHz, chloroform-d) δppm 8.11 (1H, dd, J = 3.1, 1.2 Hz), 7.49 (1H, dd, J = 5.1, 3.1 Hz), 7.43 (1H, dd, J = 5.2, 1.3Hz), 3.11 (3H, s).

4-Methanesulfonylthiophene-2-sulfonyl chloride Chlorosulfonic acid (8.11 mL, 0.12 mol) was added to 3-methanesulfonylthiophene (2.2 g, 13.56 mmol) and the suspension was added at 90 ° C. for 1 hour. Heated. The solution was cooled to a temperature of about 25 ° C. and poured onto ice (100 mL). The sulfonyl chloride was extracted into dichloromethane (3 × 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a light tan solid (3.16 g, 89% yield). . ¹ H NMR (500 MHz, chloroform-d) δppm 8.50 (1H, d, J = 1.6Hz), 8.17 (1H, d, J = 1.6Hz), 3.19 (3H, s).

N-hydroxy-4-methanesulfonylthiophene-2-sulfonamide—To a solution of aqueous hydroxylamine (50% aqueous solution 2.03 mL, 30.68 mmol) in tetrahydrofuran (12 mL) and water (3 mL) cooled to −5 ° C. 4-Methanesulfonylthiophene-2-sulfonyl chloride (3.2 g, 12.27 mmol) was added slowly while maintaining the reaction temperature below 10 ° C. The reaction is maintained at this temperature until substantially complete consumption of the sulfonyl chloride is observed by TLC (about 15 minutes), after which the reaction is diluted with diethyl ether (25 mL) and the organic portion is separated. And washed with water (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give N-hydroxysulfonamide as an off-white solid. Trituration with diethyl ether gave the title compound as an off-white solid (1.34 g, 42.4% yield). LC-MS t _R = 0.91 min, [M−H] ⁻ = 256; ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 10.02 (1H, d, J = 3.0 Hz), 9.96 (1H, d , J = 3.2Hz), 8.73 (1H, d, J = 1.6Hz), 7.98 (1H, d, J = 1.6Hz), 3.33 (3H, s).

5-Bromo-N-hydroxy-2-methoxybenzene-1-sulfonamide (17)
To a solution of aqueous hydroxylamine (50% solution 2.89 mL, 43.78 mmol) in tetrahydrofuran (30 mL) and water (5 mL) cooled to −5 ° C. while maintaining the reaction temperature below 10 ° C. 2-Methoxybenzene-1-sulfonyl chloride (5 g, 17.51 mmol) was added slowly. The reaction is maintained at this temperature until complete consumption of the sulfonyl chloride is observed by LC-MS (about 5 minutes), after which the reaction is diluted with dichloromethane (50 mL) and the organic portion is separated off. Washed with water (2 × 10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give N-hydroxysulfonamide as an off-white solid. Trituration with heptane: DCM (1: 1, v: v) gave the title compound as an off-white solid (2.94 g, 60% yield). LC-MS t _R = 1.66 min, [M−H] ⁻ = 281; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ9.68 (s, 1H), 9.39-9.17 (m, 1H), 7.85 (dd, J = 8.9, 2.6Hz, 1H), 7.80 (d, J = 2.5Hz, 1H), 7.24 (d, J = 8.9Hz, 1H), 3.90 (s, 3H).

4-Chloro-N-hydroxy-2,5-dimethylbenzene-1-sulfonamide (18)
To a solution of aqueous hydroxylamine (50% solution 3.45 mL, 52.28 mmol) in tetrahydrofuran (30 mL) and water (5 mL) cooled to −5 ° C. while maintaining the reaction temperature below 10 ° C. -2,5-Dimethylbenzene-1-sulfonyl chloride (5 g, 20.91 mmol) was added slowly. The reaction is maintained at this temperature until complete consumption of the sulfonyl chloride is observed by LC-MS (about 5 minutes), after which the reaction is diluted with dichloromethane (50 mL) and the organic portion is separated off. Washed with water (2 × 10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give N-hydroxysulfonamide as an off-white solid. Trituration with heptane: DCM (1: 1, v: v) gave the title compound as a white solid (3.26 g, 66% yield). LC-MS t _R = 1.86 min, [M−H] ⁻ = 234; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ9.59 (s, 2H), 7.78 (s, 1H), 7.52 ( s, 1H), 2.55 (s, 3H), 2.36 (s, 3H).

N, N-diethyl-5- (hydroxysulfamoyl) thiophene-2-carboxamide (19)
N, N-diethylthiophene-2-carboxamide To a solution of diethylamine (4.9 g, 68.2 mmol) in DCM (100 mL) was added triethylamine (6.9 g, 68.2 mmol) and thiophene-2-carbonyl chloride (10 g, 68.2 mmol) was added sequentially and the resulting solution was stirred at a temperature of about 25 ° C. for 8 hours. The reaction mixture is diluted with DCM (50 mL) and washed with water (2 × 50 mL), the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product as a brown liquid (11.0 g, 87% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ7.42 (1H, dd, 5.0, 1.1Hz), 7.32 (1H, dd, 3.7, 1.1Hz), 7.04 (1H, dd, 5.0, 3.6Hz), 3.54 ( 4H, q, 7.1Hz), 1.26 (6H, t, 7.1Hz).

5- (Diethylcarbamoyl) thiophene-2-sulfonyl chloride To an ice-cooled solution of N, N-diethylthiophene-2-carboxamide (15.0 g, 81.8 mmol), chlorosulfonic acid (38.2 g, 327 mmol) was added dropwise. The resulting solution was stirred at 0 ° C. for 30 minutes and then heated to 80 ° C. for 12 hours. The reaction mixture was quenched by addition to ice and the resulting acidic solution was extracted into DCM (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the sulfonyl chloride as a mixture of isomers. Obtained. Chromatography on a silica gel column eluted with 18% EtOAc: hexanes afforded the desired compound (1.9 g, 8% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ7.79 (1H, d, 4.1Hz), 7.28 (1H, t, 3.6Hz), 3.53 (4H, q, 7.1Hz), 1.28 (6H, t, 7.1Hz ).

N, N-diethyl-5- (hydroxysulfamoyl) thiophene-2-carboxamide A solution of 5- (diethylcarbamoyl) thiophene-2-sulfonyl chloride (1.8 g, 6.3 mmol) in THF (20 mL) was added. To a solution of aqueous hydroxylamine (0.5 g, 15.8 mmol) in water (5 mL) and THF (20 mL) was added while maintaining the temperature between −10 ° C. and −5 ° C. The resulting reaction was stirred at this temperature for 40 minutes, after which time the reaction was found to be substantially complete by TLC. The reaction was poured into ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as an off-white solid (1.9 g). The desired N-hydroxysulfonamide was isolated by trituration with DCM: n-pentane (2: 8; v: v) to give a white solid (1.0 g, 56% yield). ¹ H NMR (360 MHz, DMSO-d ₆ ) δ 9.90 (1H, d, 3.2 Hz) 9.85 (1H, d, 3.2 Hz) 7.59 (1H, d, 4.1 Hz) 7.45 (1H, d, 4.1 Hz) 3.45 (4H, q, 6.8 Hz) 1.16 (6H, t, 6.4 Hz); predicted value [M−H] ⁻ = 277.0317; observed value [M−H] ⁻ = 277.0316.

5-Fluoro-N-hydroxy-2-methylbenzene-1-sulfonamide (20)
To a solution of aqueous hydroxylamine (1.5 mL of 50% solution, 23.9 mmol) in tetrahydrofuran (10 mL) and water (2 mL) cooled to −5 ° C. while maintaining the reaction temperature below 10 ° C., tetrahydrofuran (2 mL ) Was slowly added in 5-fluoro-2-methylbenzene-1-sulfonyl chloride (2.0 g, 9.6 mmol). The reaction is maintained at this temperature until complete consumption of the sulfonyl chloride is observed by LC-MS (about 10 minutes), after which the reaction is diluted with diethyl ether (30 mL) and the organic portion is separated. Wash with 1M citric acid solution (10 mL), dehydrate with magnesium sulfate, filter, and concentrate under reduced pressure to give N-hydroxysulfonamide as an off-white solid (0.64 g, 32.1% yield). As obtained. ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 9.77 (1H, m), 9.72 (1H, m), 7.59 (1H, dd, 8.7, 2.0Hz), 7.49 (1H, m), 7.46 (1H, m), 2.58 (1H, d, 0.8 Hz); predicted value [M−H] ⁻ = 204.0131; observed value [M−H] ⁻ = 204.0129.

N-hydroxy-5- (morpholine-4-carbonyl) thiophene-2-sulfonamide (21)
4-[(thiophen-2-yl) carbonyl] morpholine To a solution of morpholine (3.3 mL, 37 mmol) and diisopropylethylamine (6.5 mL, 37 mmol) in dichloromethane (50 mL) cooled to 0 ° C. Carbonyl chloride (5 g, 34 mmol) was added dropwise. The reaction mixture was stirred at a temperature of about 25 ° C. for 18 hours and then quenched by adding 1N HCl solution (20 mL). The organic portion was washed with water (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (7.01 g, 65% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 7.76 (1H, dd, 5.0, 1.1Hz), 7.42 (1H, dd, 3.7, 1.2Hz), 7.12 (1H, dd, 4.9, 3.7Hz), 3.53 -3.71 (8H, m).

5-[(Morpholin-4-yl) carbonyl] thiophene-2-sulfonyl chloride Chlorosulfonic acid (45.57 mL, 684.4 mmol) was converted to 4-[(thiophen-2-yl) carbonyl] morpholine (13.5 g, 68 .44 mmol) and the suspension was heated to 100 ° C. for 2 hours. The solution was cooled to a temperature of about 25 ° C. and poured onto ice (500 mL). The sulfonyl chloride was extracted into dichloromethane (3 × 100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a mixture of isomers (16.5 g) which was converted to 0-50 Separation through a silica gel column eluted with a gradient of% ethyl acetate: heptane (4.15 g, 20.5% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 7.19 (1H, d, J = 3.7 Hz), 7.07 (1H, d, J = 3.8 Hz), 3.62 (8H, s). The other isomer (5- (morpholine-4-carbonyl) thiophene-3-sulfonyl chloride) was isolated for use in the synthesis of the corresponding N-hydroxysulfonamide (1.4 g, 6.5% yield). rate). ¹ H NMR (500 MHz, chloroform-d) δppm 8.35 (1H, d, J = 1.4Hz), 7.63 (1H, d, J = 1.3Hz), 3.78 (8H, s).

N-hydroxy-5-[(morpholin-4-yl) carbonyl] thiophene-2-sulfonamide Aqueous hydroxylamine (1.12 mL of 50% solution) in tetrahydrofuran (2 mL) and water (2 mL) cooled to -5 ° C. 16. [9] in a solution of 5-[(morpholin-4-yl) carbonyl] thiophene-2-sulfonyl chloride (2 g, 6.76 mmol) in tetrahydrofuran (10 mL) while maintaining the reaction temperature below 10 ° C. The solution was added slowly. The reaction is maintained at this temperature until complete consumption of the sulfonyl chloride is observed by LC-MS (about 10 minutes), after which the reaction is diluted with diethyl ether (30 mL) and the organic portion is separated. Washed with water (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give N-hydroxysulfonamide as an off-white solid. Trituration with heptane gave the title compound as a white solid (0.24 g, 12.4% yield). LC-MS t _R = 1.11 min, [M + H] ⁺ = 293; ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.90 (1H, s), 9.85 (1H, s), 7.60 (1H, d , J = 3.9Hz), 7.48 (1H, d, J = 3.9Hz), 3.63 (8H, s).

5- (Hydroxysulfamoyl) -N- (propan-2-yl) thiophene-2-carboxamide (22)
N- (propan-2-yl) thiophene-2-carboxamide To a solution of isopropylamine (3.2 mL, 37 mmol) and diisopropylethylamine (5.3 mL, 37 mmol) in dichloromethane (50 mL) cooled to 0 ° C. was added thiophene- 2-Carbonyl chloride (5 g, 34 mmol) was added dropwise. The reaction mixture was stirred at a temperature of about 25 ° C. for 18 hours and then quenched by the addition of 1N HCl solution. The organic portion was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (5.78 g, 99% yield).

5-[(propan-2-yl) carbamoyl] thiophene-2-sulfonyl chloride Chlorosulfonic acid (23 mL, 337 mmol) was converted to N- (propan-2-yl) thiophene-2-carboxamide (5.7 g, 33.7 mmol). And the suspension was heated to 100 ° C. for 90 minutes. The solution was cooled to a temperature of about 25 ° C. and poured onto ice (300 mL). The sulfonyl chloride was extracted into dichloromethane (3 × 100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a mixture of isomers, which was 0-30% ethyl acetate: heptane. Was separated by a silica gel column eluted with a gradient of (1.6 g, 17.7% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 7.97 (1H, d, 6.7Hz), 7.30 (1H, d, 3.8Hz), 6.83 (1H, d, 3.8Hz), 3.71-3.82 (1H, m ), 0.90 (6H, d, 6.7Hz). The other isomer (5-[(propan-2-yl) carbamoyl] thiophene-3-sulfonyl chloride) was isolated from this synthesis and used to make the corresponding N-hydroxysulfonamide (2. 3 g, 25.5% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 8.36 (1H, d, 7.8Hz), 7.91 (1H, d, 1.2Hz), 7.64 (1H, d, 1.2Hz), 4.01 (1H, heptad, 6.8Hz), 1.13 (6H, d, 6.6Hz).

5- (hydroxysulfamoyl) -N- (propan-2-yl) thiophene-2-carboxamide-aqueous hydroxylamine (50% solution 0) in tetrahydrofuran (10 mL) and water (1.6 mL) cooled to -5 ° C. To a solution of .99 mL, 15 mmol), subdivide 5-[(propan-2-yl) carbamoyl] thiophene-2-sulfonyl chloride (1.6 g, 5.98 mmol) while maintaining the reaction temperature below 10 ° C. And slowly added. The reaction is maintained at this temperature until complete consumption of the sulfonyl chloride is observed by LC-MS (about 10 minutes), after which the reaction is diluted with diethyl ether (30 mL) and the organic portion is separated. Washed with water (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give N-hydroxysulfonamide as a white solid (0.7 g, 44% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.86 (1H, br.s.), 9.80 (1H, s), 8.57 (1H, d, 7.8Hz), 7.81 (1H, d, 4.0Hz), 7.63 (1H, d, 4.1 Hz), 3.95-4.21 (1H, m), 1.16 (6H, d, 6.6 Hz); predicted value [M−H] ⁻ = 263.0160; observed value [M−H] ⁻ = 263.0161.

N-hydroxy-5-methanesulfonylthiophene-2-sulfonamide (23)
5-Methanesulfonylthiophene-2-sulfonyl chloride Chlorosulfonic acid (14.4 mL, 215 mmol) was added to 2-methanesulfonylthiophene (5.0 g, 30.8 mmol) and the reaction was heated to 90 ° C. for 1 hour. . The resulting colored solution is poured onto ice and the organic portion is extracted into DCM (2 × 30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired sulfonyl chloride, which is an undesirable 2,4 isomer. And was used directly for the synthesis of the corresponding N-hydroxysulfonamide (4.6 g, 26% yield). LC-MS t _R = 1.92 min; [M-Cl + OH + H] ⁺ = 240.80; ¹ H NMR (250 MHz, DMSO-d ₆ ) d 7.57 (1H, d, 3.8 Hz), 7.18 (1H, d , 3.8Hz), 3.31 (3H, s).

N-hydroxy-5-methanesulfonylthiophene-2-sulfonamide—To a solution of aqueous hydroxylamine (1.6% of 50% aqueous solution, 24 mmol) in THF (10 mL) and water (2 mL) at −10 ° C., the internal temperature was − While maintaining at 5 ° C., 5-methanesulfonylthiophene-2-sulfonyl chloride (1.3 g, 4.8 mmol) was added in small portions. Stirring was continued at low temperature until complete consumption of the sulfonyl chloride was observed by LC-MS. DCM (20 mL) was added and the reaction was washed with water (5 mL). The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired N-hydroxysulfonamide as an off-white solid as a mixture with the undesired 2,4 isomer. Separation of the two isomers was achieved by acidic preparative reverse phase HPLC to give the desired 2,5-isomer (0.5 g, 41% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ10.09 (2H, s), 7.91 (1H, d, 4.0Hz), 7.75 (1H, d, 4.0Hz), 3.48 (s, 3H).

N-hydroxy-2,1,3-benzothiadiazole-4-sulfonamide (24)
To a solution of aqueous hydroxylamine (50% solution 0.7 mL, 10.65 mmol) in tetrahydrofuran (6 mL) and water (1 mL) cooled to −5 ° C. while maintaining the reaction temperature below 10 ° C., 2,1 , 3-Benzothiadiazole-4-sulfonyl chloride (1.0 g, 4.3 mmol) was added slowly. The reaction is maintained at this temperature until complete consumption of the sulfonyl chloride is observed by LC-MS (about 5 min), after which the reaction is diluted with dichloromethane (20 mL) and the organic portion is separated off. Washed with water (2 × 5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give N-hydroxysulfonamide as a yellow solid, which was triturated with heptane and dried under reduced pressure (0.59 g, 59.9% yield). LC-MS t _R = 1.26 min, [M−H] ⁻ = 230; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ9.73 (s, 2H), 8.45 (dd, J = 8.8, 0.9 Hz, 1H), 8.28 (dd, J = 7.0, 0.9 Hz, 1H), 7.92 (dd, J = 8.8, 7.1 Hz, 1H); predicted value [M−H] ⁻ = 2299.9694; observed value [M -H] ^- = 2299.9687.

N-hydroxy-2-methoxybenzene-1-sulfonamide (25)
To an aqueous solution (1.6 mL) of hydroxylamine HCl (1.31 g, 18.9 mmol) cooled to 0 ° C., an aqueous solution (2.4 mL) of potassium carbonate (2.62 g, 18.9 mmol) was added. It was added dropwise while maintaining between 5 ° C and 15 ° C. The reaction mixture was stirred for 15 minutes, at which point tetrahydrofuran (8 mL) and methanol (2.0 mL) were added. 2-Methoxybenzene-1-sulfonyl chloride (1.96 g, 9.48 mmol) is added in small portions while maintaining the temperature below 15 ° C. until substantially complete consumption of the sulfonyl chloride is observed by TLC. The reaction mixture was stirred at 5 ° C. The resulting suspension was concentrated under reduced pressure to remove any volatiles and the aqueous suspension was extracted with diethyl ether (2 × 50 mL). The organic portion was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give N-hydroxysulfonamide as a white solid (0.4 g, 21% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 9.53 (1H, d, J = 3.4Hz), 8.99 (1H, d, J = 3.4Hz), 7.76 (1H, dd, J = 7.8, 1.7Hz) , 7.62-7.67 (1H, m), 7.23 (1H, d, J = 8.3Hz), 7.11 (1H, t, J = 7.6Hz), 3.89 (3H, s); Predicted value [M−H] ⁻ = 202.0174; observed value [M−H] ⁻ = 202.0155.

N-hydroxypyridine-3-sulfonamide (26)
A solution of aqueous hydroxylamine (50% solution 11.07 mL, 167.5 mmol) in tetrahydrofuran (40 mL) cooled to −15 ° C. to pyridine-3-sulfonyl chloride (11.9 g, 67 mmol) in THF (30 mL). During the addition, the temperature is maintained below 2 ° C.-3 ° C. and stirring is continued for an additional 10 minutes, after which LC-MS confirms complete consumption of the sulfonyl chloride. Indicated. Dichloromethane (50 mL) and water (25 mL) were added, the mixture was shaken, the two layers were separated, and the aqueous layer was further extracted with dichloromethane (1 × 50 mL). The combined organic layers were dried over magnesium sulfate and concentrated to give a solid insoluble in dichloromethane, triturated with dichloromethane: heptane (1: 1 v: v) to give the title compound as a white solid (3.47 g, 29 0.7% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.85 (1H, d, J = 2.8Hz), 9.80 (1H, s), 8.95 (1H, d, J = 2.2Hz), 8.87 (1H, dd, J = 4.8, 1.5Hz), 8.20 (1H, dt, J = 8.0, 1.9Hz), 7.69 (1H, dd, J = 8.0, 4.9Hz), predicted value [M + H] ⁺ = 175.0177; observed value [ M + H] ^< +> = 175.0172.

N-hydroxy-3,5-dimethyl-1,2-oxazole-4-sulfonamide (27)
To a solution of aqueous hydroxylamine (50% solution 22.79 mL, 0.35 mol) in tetrahydrofuran (160 mL) and water (27 mL) cooled to −5 ° C. while maintaining the reaction temperature below 10 ° C., dimethyl-1 , 2-Oxazole-4-sulfonyl chloride (27 g, 138.02 mmol) was added in portions and slowly added. The reaction is maintained at this temperature until complete consumption of the sulfonyl chloride is observed by LC-MS (about 10 minutes), after which the reaction is diluted with dichloromethane (250 mL) and the organic portion is separated. , Washed with water (2 × 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give N-hydroxysulfonamide as a white solid. Trituration with heptane gave the title compound as a white solid (16.16 g, 60.9% yield). LC-MS t _R = 1.08 min, [M + H] ⁺ = 193; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ9.79 (d, J = 2.8 Hz, 1H), 9.64 (d, J = 2.8Hz, 1H), 2.60 (s, 3H), 2.35 (s, 3H).

N-hydroxy-5- (morpholine-4-carbonyl) thiophene-3-sulfonamide (28)
5- (Morpholine-4-carbonyl) thiophene-3-sulfonyl chloride 4- (thiophene-2-carbonyl) morpholine (15 g, 76.04 mmol) to chlorosulfonic acid (35. 44 g, 304.18 mmol) was added dropwise. The temperature was maintained at 0 ° C. for 30 minutes and then stirred at a temperature of about 25 ° C. for 1 hour. No reaction was observed, and the temperature was further raised to 80 ° C. for 12 hours. The resulting slurry was poured onto ice water (500 mL), extracted into dichloromethane (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the compound as a mixture of isomers. Chromatography of the sulfonyl chloride on a silica gel column eluted with EtOAc: hexane (30% EtOAc) gave the title compound as a colorless oil (3.0 g, 13.34% yield). LC-MS t _R = 1.18 min, [M + H] ⁺ = 293; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (d, J = 1.3 Hz, 1H), 7.62 (d, J = 1.4 Hz , 1H), 4.12 (d, J = 7.1Hz, 1H), 3.78 (s, 8H), 2.09 (s, 1H), 2.05 (s, 1H), 1.26 (t, J = 7.1Hz, 1H).

1-N-hydroxy-2-N- (propan-2-yl) benzene-1,2-disulfonamide (29)
2-Fluoro-N- (propan-2-yl) benzene-1-sulfonamide A solution of 2-fluorobenzenesulfonyl chloride (3.6 mL, 27.4 mmol) in DCM (50 mL) was cooled at 0 ° C. 2-Amine (3.5 mL, 41.2 mmol) was added followed by pyridine (3.3 mL, 41.2 mmol). The reaction was warmed to a temperature of about 25 ° C. and stirring was continued for 1 hour. The reaction was quenched by the addition of 1M sodium hydroxide solution (10 mL) and the resulting organic portion was washed with water (10 mL), 1M aqueous HCl (10 mL) and brine (10 mL), then dried over magnesium sulfate. Filtration and concentration of the filtrate under reduced pressure gave an oil that solidified upon standing (4.95 g, 83% yield). ¹ HN MR (250 MHz, chloroform-d) δ7.91 (1H, td, 7.6, 1.8Hz), 7.64-7.48 (1H, m), 7.26 (2H, m), 4.65 (1H, d, 6.5Hz) , 3.63-3.40 (1H, m, 6.7Hz), 1.10 (6H, d, 6.5Hz).

2- (Benzylsulfanyl) -N- (propan-2-yl) benzene-1-sulfonamide To a solution of phenylmethanethiol (648 μL, 5.52 mmol) in DMSO (8 mL) was added NaOH (0.28 g, 6. 9 mmol) was added and the reaction was stirred for 20 minutes (until the NaOH pellets dissolved). 2-Fluoro-N- (propan-2-yl) benzene-1-sulfonamide (645 μL, 4.6 mmol) was added and the reaction mixture was heated at 75 ° C. for 18 hours. The reaction was cooled to a temperature of about 25 ° C. and water (1 mL) was added. The reaction was subsequently acidified with conc. HCl and the organic portion was extracted into ethyl acetate (2 × 10 mL). The combined organics were washed with water (5 mL) and brine (5 mL), then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give an oil that was 7-50% ethyl acetate: Chromatography on a silica gel column eluted with a heptane gradient afforded the desired compound as a yellow oil which solidified upon standing followed by trituration with heptane (1. 1 g, 71% yield). ¹ H NMR (250 MHz, chloroform-d) δ8.14-8.00 (1H, m), 7.45-7.23 (8H, m), 5.35 (1H, d, 7.2Hz), 4.24 (2H, s), 3.37 ( 1H, 7-wire, 6.6Hz), 0.98 (6H, d, 6.5Hz)

2-[(propan-2-yl) sulfamoyl] benzene-1-sulfonyl chloride 2- (benzylsulfanyl) -N- (propane-) in acetonitrile (46 mL), acetic acid (1.8 mL) and water (1.2 mL) A solution of 2-yl) benzene-1-sulfonamide (1.5 g, 4.67 mmol) was cooled at 0 ° C. (external) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.84 g, 9.33 mmol) was added in one portion and the reaction was stirred at 0 ° C. for 1 hour. The reaction is diluted with DCM (50 mL) and the organic portion is washed with saturated aqueous sodium bicarbonate (10 mL) and brine (20 mL), then dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a colorless oil. Which was chromatographed on a silica gel column eluted with a gradient of 5-40% heptane: EtOAc to give the title compound as a white solid (0.8 g, 52% yield). ¹ H NMR (250 MHz, chloroform-d) δ 8.36 (2H, dt, 7.9, 1.5Hz), 7.95-7.77 (2H, m), 5.50 (1H, d, 7.3Hz), 3.66-3.42 (1H, m), 1.06 (6H, d, 6.6Hz).

1-N-hydroxy-2-N- (propan-2-yl) benzene-1,2-disulfonamide Aqueous hydroxylamine (50% solution 0.8 mL, 11.7 mmol) in THF (6 mL) and water (1. 5 mL) was added and the solution was cooled to −10 ° C. To this cold solution was added 2-[(propan-2-yl) sulfamoyl] benzene-1-sulfonyl chloride (1... In THF (3 mL) while maintaining the temperature below 2-3 ° C. during the addition. 4 g, 4.7 mmol) solution was added dropwise. The reaction mixture was stirred at 0 ° C. for 10 minutes, at which point LC-MS showed complete consumption of the sulfonyl chloride. The reaction was diluted with DCM (10 mL) and washed with water (2 mL). The aqueous layer was further extracted into DCM (10 mL) and the organic layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an oil. This oil was dissolved in a minimum amount of DCM and then heptane was added, at which point a white solid precipitated. The precipitated solid was collected by filtration, washed with heptane and dried under reduced pressure to give 1-N-hydroxy-2-N- (propan-2-yl) benzene-1,2-disulfonamide as a white solid (0 0.6 g, 42% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δ10.06 (1H, d, 3.4Hz), 9.09 (1H, d, 3.5Hz), 8.25-8.08 (2H, m), 8.01-7.78 (2H, m ), 7.02 (1H, d, 7.5Hz), 3.41 (1H, dd, 13.5, 6.8Hz), 0.98 (6H, d, 6.5Hz).

5-Chloro-N-hydroxy-1,3-dimethyl-1H-pyrazole-4-sulfonamide (30)
To a solution of aqueous hydroxylamine (1.4 mL of 50% solution, 0.02 mol) in tetrahydrofuran (12 mL) and water (2 mL) cooled to −5 ° C. while maintaining the reaction temperature below 10 ° C., 5-chloro -1,3-Dimethyl-1H-pyrazole-4-sulfonyl chloride (2 g, 8.7 mmol) was added slowly. The reaction is maintained at this temperature until substantially complete consumption of the sulfonyl chloride is observed by TLC (about 5 minutes), after which the reaction is diluted with dichloromethane (20 mL) and the organic portion is separated. Wash with water (2 × 5 mL), dehydrate with sodium sulfate, filter and concentrate under reduced pressure. The solid was isolated by trituration from heptane: diethyl ether (1: 1 v: v) to give N-hydroxysulfonamide as a white solid (1.16 g, 58% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.56 (1H, d, 2.1Hz), 9.39 (1H, d, 2.3Hz), 3.77 (3H, s), 2.30 (3H, s), predicted value [ M−H] ⁻ = 223.9897; observed value [M−H] ⁻ = 2233.9893.

N-hydroxy-1-methyl-1H-pyrazole-4-sulfonamide (31)
To a solution of aqueous hydroxylamine (0.91 mL of 50% solution, 13.84 mmol) in tetrahydrofuran (3 mL) and water (1 mL) cooled to −5 ° C. while maintaining the reaction temperature below 10 ° C. -1H-pyrazole-4-sulfonyl chloride (1 g, 5.54 mmol) was added slowly. The reaction is maintained at this temperature until substantially complete consumption of the sulfonyl chloride is observed by TLC (about 5 minutes), after which the reaction is diluted with dichloromethane (10 mL, then 200 mL due to poor solubility). The organic portion was separated, washed with water (2 × 5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give N-hydroxysulfonamide as a white solid (641 mg, 65% yield). As obtained. LC-MS t _R = 0.38 min, [M + H] ⁺ = 179; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ9.52 (s, 1H), 9.26 (s, 1H), 8.26 (s, 1H), 7.72 (s, 1H), 3.89 (s, 3H).

N-hydroxypyridine-2-sulfonamide (32)
An aqueous solution (4.8 mL) of potassium carbonate (6.2 g, 45.0 mmol) was added to an aqueous solution (7.2 mL) of hydroxylamine hydrochloride (3.11 g, 45.0 mmol) at 0 ° C., and the internal reaction temperature was 5 ° C. Added dropwise while maintaining between -15 ° C. Tetrahydrofuran (24 mL) and methanol (6 mL) are added in portions, followed by pyridine-2-sulfonyl chloride (4.0 g, 21.5 mmol) while maintaining the temperature below 15 ° C. The reaction mixture was stirred at a temperature of about 25 ° C. until complete consumption was observed. The resulting suspension was concentrated to remove any volatiles, the aqueous suspension was diluted with diethyl ether (50 mL), and the reaction was washed with water (10 mL). The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. Recrystallization of the desired compound was achieved from diethyl ether and the expected product was obtained as a white solid (1.2 g, 31% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 9.98 (1H, d, 2.9Hz), 9.60 (1H, d, 2.9Hz), 8.78 (1H, ddd, 4.6, 1.7, 1.0Hz), 8.10 (1H , dd, 7.6, 1.7 Hz), 8.01 (1H, dt, 7.8, 1.0 Hz), 7.71 (1H, ddd, 7.6, 4.6, 1.2 Hz); predicted value [M−H] ⁻ = 173.0021; observed value [M−H] ⁻ = 173.0001.

3-Bromo-N-hydroxypyridine-2-sulfonamide (33)
3-Bromo-2-mercaptopyridine In a pressure tube, a solution of 2-chloro-3-bromopyridine (0.5 g, 2.5 mmol) in ethanol (5 mL) and water (1 mL) was added to sodium hydrogen sulfide (0.5 mL, 2.5 mmol). 0.73 g, 13 mmol) was added. The reaction was heated to 140 ° C. for 18 hours, after which no starting material remained. The product was taken up in ethyl acetate (10 mL) and washed with a solution of 10% potassium carbonate solution (5 mL). The resulting aqueous extract was acidified with 6N hydrochloric acid to pH 5 and extracted with ethyl acetate (2 × 25 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure (0.41 g, 84% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 8.05 (1H, dd, 7.5, 1.6 Hz), 7.75 (1H, d, 5.1 Hz), 6.66 (1H, dd, 7.6, 6.1 Hz).

3-Bromopyridine-2-sulfonyl chloride A solution of 2-mercapto-3-bromo-pyridine (5.3 g, 27.5 mmol) in concentrated hydrochloric acid (20 mL) cooled to 0 ° C. had substantially complete saturation. Chlorine gas was added at a constant rate until achieved. When the reaction was complete, sulfonyl chloride was added to ice water and the resulting aqueous phase was extracted with dichloromethane (3 × 100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. This sulfonyl chloride was used directly in the synthesis of the corresponding N-hydroxysulfonamide.

3-Bromo-N-hydroxypyridine-2-sulfonamide An aqueous solution of potassium carbonate (3.21 g, 23.3 mmol) in an aqueous solution (2.4 mL) of hydroxylamine hydrochloride (1.61 g, 23.3 mmol) at 0 ° C. (3.6 mL) was added dropwise while maintaining the internal reaction temperature between 5 ° C and 15 ° C. Tetrahydrofuran (12 mL) and methanol (3 mL), followed by 3-bromopyridine-2-sulfonyl chloride (3.0 g, 11.65 mmol) were added in small portions, maintaining the temperature below 15 ° C., and the sulfonyl chloride by TLC was added. The reaction mixture was stirred at a temperature of about 25 ° C. until substantially complete consumption was observed. The resulting suspension was concentrated to remove any volatiles, the aqueous suspension was diluted with diethyl ether (50 mL), and the reaction was washed with water (10 mL). The aqueous portion was re-extracted with diethyl ether (2 × 15 mL) and the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. Chromatography of N-hydroxysulfonamide on a silica gel column eluted with a heptane: ethyl acetate gradient gave the expected product as a white solid (0.4 g, 5% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 10.34 (1H, d, 2.9Hz), 9.62 (1H, d, 2.9Hz), 8.71 (1H, dd, 4.5, 1.3Hz), 8.37 (1H, dd , 8.2, 1.3 Hz), 7.62 (1H, dd, 8.1, 4.4 Hz); predicted value [M−H] ⁻ = 250.9126; observed value [M−H] ⁻ = 250.9135.

4-N-hydroxythiophene-2,4-disulfonamide (34)
4-N-hydroxythiophene-2,4-disulfonamide was prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide (1 g, 3 g .8 mmol) (0.25 g, 26 5 yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δ10.05 (s, 2H), 9.99 (s, 1H), 9.80 (s, 1H), 8.60 (1H, d, J 1.5Hz), 7.83 (1H, d, 1.5Hz).

N-hydroxy-4- (morpholine-4-carbonyl) thiophene-2-sulfonamide (35)
To a hydroxylamine aqueous solution (50% solution 0.3 mL, 4.2 mmol) was added THF (3 mL) and water (0.5 mL) and the solution was cooled to −10 ° C. To this cold solution, add 4- (morpholine-4-carbonyl) thiophene-2-sulfonyl chloride (0.5 g, 1.7 mmol) in small portions while maintaining the temperature below 2-3 ° C. during the addition. Added. The reaction mixture was stirred at 0 ° C. for 10 minutes, at which point LC-MS showed complete consumption of the sulfonyl chloride. The reaction was diluted with DCM (10 mL) and washed with water (2 mL). The aqueous layer was further extracted into DCM (10 mL) and the organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. This compound was triturated with diethyl ether to give the desired compound as a white solid (0.2 g, 40% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.88 (1H, d, 2.9Hz), 9.80 (1H, d, 2.9Hz), 8.22 (1H, s), 7.67 (1H, s), 3.44-3.71 (8H, m); predicted value [M−H] ⁻ = 291.0109; observed value [M−H] ⁻ = 291.0110.

N-hydroxy-5- [5- (trifluoromethyl) -1,2-oxazol-3-yl] thiophene-2-sulfonamide (36)
N-hydroxy-5- [5- (trifluoromethyl) -1,2-oxazol-3-yl] thiophene-2-sulfonamide is a method described herein for the synthesis of N-hydroxysulfonamide. From 5- [5- (trifluoromethyl) -1,2-oxazol-3-yl] thiophene-2-sulfonyl chloride (1 g, 3.2 mmol) and triturated with diethyl ether to give the desired compound Was obtained as a white solid (0.7 g, 71% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.98 (1H, s), 9.95 (1H, br.s.), 8.17 (1H, s), 7.93 (1H, d, 4.0Hz), 7.78 (1H , d, 3.8 Hz); predicted value [M−H] ⁻ = 312.9565; observed value [M−H] ⁻ = 312.9564.

6-Chloro-N-hydroxy-7H, 7aH-imidazo [2,1-b] [1,3] thiazole-5-sulfonamide (37)
6-Chloro-N-hydroxy-7H, 7aH-imidazo [2,1-b] [1,3] thiazole-5-sulfonamide is a method described herein for the synthesis of N-hydroxysulfonamide. Was synthesized from 6-chloro-7H, 7aH-imidazo [2,1-b] [1,3] thiazole-5-sulfonyl chloride (0.1 g, 0.4 mmol) and powdered from diethyl ether to give the desired Was obtained as a white solid (0.03 g, 30% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 10.02 (1H, br.s.), 9.84 (1H, s), 7.88 (1H, d, 4.6Hz), 7.61 (1H, d, 4.4Hz).

N-hydroxy-5- (1,2-oxazol-5-yl) thiophene-2-sulfonamide (38)
N-hydroxy-5- (1,2-oxazol-5-yl) thiophene-2-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide. -Oxazol-5-yl) thiophene-2-sulfonyl chloride (5.0 g, 20 mmol) and powdered with heptane gave the desired compound as a white solid (2.6 g, 53% yield). . ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.96 (1H, s), 9.92 (1H, br.s.), 8.74 (1H, s), 7.79 (1H, d, 3.8Hz), 7.73 (1H , d, 4.0 Hz), 7.13 (1H, s); predicted value [M−H] ⁻ = 244.9691; observed value [M−H] ⁻ = 244.9702.

4-Fluoro-N-hydroxy-2-methylbenzene-1-sulfonamide (39)
4-Fluoro-N-hydroxy-2-methylbenzene-1-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide. Synthesized from chloride (1.0 g, 4.8 mmol) and triturated with heptane to give the desired compound as a white solid (0.65 g, 65% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) d 9.60 (1H, s), 9.59 (1H, s), 7.89 (1H, dd, 8.7, 6.0Hz), 7.28-7.33 (1H, m), 7.26 ( 1H, t, 8.5 Hz), 2.60 (3H, s); predicted value [M−H] ⁻ = 204.0131; observed value [M−H] ⁻ = 204.0138.

N-hydroxy-5- (1,3-oxazol-5-yl) thiophene-2-sulfonamide (40)
N-hydroxy-5- (1,3-oxazol-5-yl) thiophene-2-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide. Prepared from -oxazol-5-yl) -2-thiophenesulfonyl chloride (0.02 g, 1%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.91 (1H, s), 9.82 (1H, br.s.), 8.51 (1H, s), 7.77 (1H, s), 7.66 (1H, d, 3.7Hz), 7.56 (1H, d, 3.5Hz).

N-hydroxy-2,5-dimethylthiophene-3-sulfonamide (41)
N-hydroxy-2,5-dimethylthiophene-3-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide, 2,5-dimethyl-3-thiophenesulfonyl chloride (2. (0 g, 9.5 mmol) and triturated with heptane to give the desired compound as a yellow solid (0.5 g, 25%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.53 (1H, d, 3.1 Hz), 9.39 (1H, d, 3.1 Hz), 6.89 (1H, s), 2.57 (3H, s), 2.38 (3H s); predicted value [M + H] ⁺ = 208.0102; observed value [M + H] ⁺ = 208.0374.

Methyl 5- (hydroxysulfamoyl) -4-methylthiophene-2-carboxylate (42)
Methyl 5- (hydroxysulfamoyl) -4-methylthiophene-2-carboxylate is prepared according to the method described herein for the synthesis of N-hydroxysulfonamide, methyl 5- (chlorosulfonyl) -4- Prepared from methyl-2-thiophenecarboxylate (2.0 g, 7.9 mmol) and triturated with diethyl ether: heptane to give the desired compound as a white solid (0.96 g, 49%). ¹ H NMR (500 MHz, DMSO-d ₆ ) 9.91 (1H, s), 9.89 (1H, br.s.), 7.74 (1H, s), 3.85 (3H, s), 2.44 (3H, s); Expected value [M−H] ⁻ = 2499.9844; observed value [M−H] ⁻ = 249.9984.

5- (Benzenesulfonyl) -N-hydroxythiophene-2-sulfonamide (43)
5- (Benzenesulfonyl) -N-hydroxythiophene-2-sulfonamide is prepared according to the method described herein for the synthesis of N-hydroxysulfonamide (5- (benzenesulfonyl) thiophene-2-sulfonyl chloride ( 2.5 g, 7.7 mmol) and chromatographed on a silica gel column eluted with a heptane: ethyl acetate gradient and then triturated with heptane to give the desired compound as a white solid (1.0 g, 40% yield). ) Was obtained. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 10.12 (1H, d, 2.9Hz), 10.05 (1H, d, 2.9Hz), 8.06 (2H, d, 8.2Hz), 7.94 (1H, d, 4.0 Hz), 7.77 (1H, d, 7.3 Hz), 7.64-7.73 (3H, m); predicted value [M−H] ⁻ = 317.9565; observed value [M−H] ⁻ = 317.9550.

N-hydroxy-5- (1,2-oxazol-3-yl) thiophene-2-sulfonamide (44)
N-hydroxy-5- (1,2-oxazol-3-yl) thiophene-2-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide. Synthesis from -oxazol-3-yl) thiophene-2-sulfonyl chloride (0.25 g, 1.0 mmol) gave the desired compound as a white solid (0.18 g, 71% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) d ppm 9.95 (1H, d, 2.4Hz), 9.91 (1H, d, 2.7Hz), 8.75 (1H, s), 7.79 (1H, d, 4.0Hz) , 7.73 (1H, d, 3.8 Hz), 7.14 (1H, s); predicted value [M−H] ⁻ = 244.9691; observed value [M−H] ⁻ = 244.9693.

5-Bromo-N-hydroxythiophene-2-sulfonamide (45)
5-Bromo-N-hydroxythiophene-2-sulfonamide is obtained from 5-bromothiophenesulfonyl chloride (2.0 g, 7.6 mmol) according to the method described herein for the synthesis of N-hydroxysulfonamide. Prepared and triturated from diethyl ether to give the desired compound as a white solid (1.2 g, 60%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.88 (1H, s), 9.80 (1H, br.s.), 7.49 (1H, d, 4.0Hz), 7.40 (1H, d, 3.9Hz); Expected value [M−H] ⁻ = 255.838; Observed value [M−H] ⁻ = 255.8727.

3,5-Dibromo-N-hydroxythiophene-2-sulfonamide (46)
3,5-Dibromothiophene-2-sulfonyl chloride To a solution of 2,4-dibromothiophene (2.0 g, 8.2 mmol) in DCM (10 mL) cooled to 0 ° C. was added chlorosulfonic acid (2.9 g, 24 mmol). ) Was added dropwise. Stirring is continued for an additional 3 hours, after which the reaction is added to ice and the organic portion is extracted into DCM (3 × 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired sulfonyl chloride. Which was used directly in the synthesis of the corresponding N-hydroxysulfonamide (1.8 g, 63% yield); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.15 (1H, s). .

3,5-Dibromo-N-hydroxythiophene-2-sulfonamide 3,5-Dibromo-N-hydroxythiophene-2-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide. , 3,5-dibromothiophene-2-sulfonyl chloride (1.8 g, 5.2 mmol) and chromatographed on a silica gel column eluted with heptane: ethyl acetate (1: 1 v: v) and then diethyl ether : Triturated from heptane to give the desired compound as a white solid (0.7 g, 40% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 10.02 (1H, d, 2.9 Hz), 9.93 (1H, d, 2.9 Hz), 7.59 (1H, s); predicted value [M−H] ⁻ = 333 Observed value [M−H] ⁻ = 3333.7949.

5-Chloro-N-hydroxy-4-nitrothiophene-2-sulfonamide (47)
5-Chloro-N-hydroxy-4-nitrothiophene-2-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide. Chromatography on a silica gel column prepared from chloride (2.0 g, 7.6 mmol) and eluted with heptane: ethyl acetate (1: 7 v: v) gave the desired compound as an orange solid (0.95 g, 48% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 10.19 (1H, d, 3.6 Hz), 8.05 (1H, s); predicted value [M−H] ⁻ = 256.9094; observed value [M−H] ^- = 256.9087.

3-Chloro-N-hydroxythiophene-2-sulfonamide (48)
3 Chloro-thiophene-2-sulfonyl chloride To a solution of 3-chlorothiophene (20 g, 0.17 mol) in DCM (40 mL) cooled to 0 ° C., chlorosulfonic acid (34 mL, 0.51 mol) was added and stirred 2 The reaction mixture was then poured onto ice and the resulting solution was extracted into DCM (3 × 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired compound. This was used directly in the next step (3.5 g, 20%). ¹ H NMR (500 MHz, chloroform-d) δ ppm 7.75 (1H, d, 5.3 Hz), 7.15 (1H, d, 5.3 Hz).

3-Chloro-N-hydroxythiophene-2-sulfonamide 3-Chloro-N-hydroxythiophene-2-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide. Prepared from thiophene-2-sulfonyl chloride (3.0 g, 13.8 mmol) and recrystallized from 5% ethyl acetate: heptane to give the desired compound as a white solid (1.39 g, 46% yield). . ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.95 (1H, s.), 9.90 (1H, br.s.), 8.16 (1H, d, 5.4Hz), 7.35 (1H, d, 5.2Hz) Predicted value [M−H] ⁻ = 211.9243; observed value [M−H] ⁻ = 211.9241.

N-hydroxy-2,5-dimethylbenzene-1-sulfonamide (49)
N-hydroxy-2,5-dimethylbenzene-1-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide (2,5-dimethylbenzene-1-sulfonyl chloride (1. Prepared from 0 g, 4.9 mmol) to give the desired compound as a white solid (0.6 g, 60% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 9.48-9.54 (2H, m), 7.66 (1H, d, 1.2Hz), 7.34-7.40 (1H, m), 7.25-7.31 (1H, m), 2.54 (3H, s), 2.34 (3H, s); predicted value [M−H] ⁻ = 200.0381; observed value [M−H] ⁻ = 200.0382.

5-Chloro-N-hydroxy-2,1,3-benzoxadiazole-4-sulfonamide (50)
5-Chloro-N-hydroxy-2,1,3-benzoxadiazole-4-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide, Prepared from 1,3-benzooxadiazole-4-sulfonyl chloride (1 g, 3.9 mmol) and chromatographed on a silica gel column eluted with heptane: ethyl acetate (1: 1 v: v) to give the desired The compound was obtained as an off-white solid (0.04 g, 5% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 10.19 (1H, d, 2.9Hz), 9.95 (1H, d, 2.9Hz), 8.45 (1H, d, 9.4Hz), 7.82 (1H, d, 9.4 Hz).

4- (Benzenesulfonyl) -N-hydroxythiophene-2-sulfonamide (51)
4- (Benzenesulfonyl) -N-hydroxythiophene-2-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide (4- (benzenesulfonyl) thiophene-2-sulfonyl chloride ( 1.0 g, 3.1 mmol) and chromatographed on a silica gel column eluted with 30% ethyl acetate: heptane to give the desired compound as an off-white solid (0.51 g, 51% yield). It was. ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 10.05 (1H, br.s), 9.44 (1H, s), 8.84 (1H, s), 8.09 (1H, m,), 8.00 (1H, m, ), 7.87 (1H, m,), 7.71 (3H, m,); predicted value [M−H] ⁻ = 317.9565; observed value [M−H] ⁻ = 317.9602.

N-hydroxy-3,4-dimethoxybenzene-1-sulfonamide (52)
N-hydroxy-3,4-dimethoxybenzene-1-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide, 3,4-dimethoxybenzene-1-sulfonyl chloride (2 g, 8.46 mmol) and triturated with diethyl ether: heptane (0.3 g, 15% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.48 (1H, d, 3.5Hz), 9.40 (1H, d, 3.5Hz), 7.42 (1H, dd, 8.4Hz, 2.1Hz), 7.33 (1H, d, 2.0 Hz), 7.16 (1H, d, 8.5 Hz), 3.85 (1H, s), 3.81 (1H, s,); predicted value [M−H] ⁻ = 232.028; observed value [M−H ] ⁻ = 232.0285.

N-hydroxy-2,3,5,6-tetramethylbenzene-1-sulfonamide (53)
N-hydroxy-2,3,5,6-tetramethylbenzene-1-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide. Prepared from methylbenzene-1-sulfonyl chloride (2 g, 8.6 mmol) to give the desired compound as a white solid (0.7 g, 34% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 9.52 (1H, br.s), 9.36 (1H, s), 7.30 (1H, s), 2.50 (6H, s), 2.27 (6H, s); Expected value [M−H] ⁻ = 228.0694; observed value [M−H] ⁻ = 228.074.

N-hydroxy-3,5-bis (trifluoromethyl) benzene-1-sulfonamide (54)
N-hydroxy-3,5-bis (trifluoromethyl) benzene-1-sulfonamide is prepared according to the method described herein for the synthesis of N-hydroxysulfonamide and 3,5-bis (trifluoromethyl). ) Prepared from benzene-1-sulfonyl chloride and triturated with diethyl ether: heptane to give the desired compound as a white solid (0.48 g, 24% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 9.99 (2H, s), 8.58 (1H, s), 8.37 (2H, s); predicted value [M−H] ⁻ = 3077.9816; observed value [ M−H] ⁻ = 307.9823.

4-Chloro-3- (hydroxysulfamoyl) benzoic acid methyl ester (55)
Methyl 4-chloro-3- (chlorosulfonyl) benzoate With stirring, MeOH (20 mL) was added to 4-chloro-3- (chlorosulfonyl) benzoyl chloride (2 g, 7.3 mmol). After 10 minutes, the reaction was concentrated under reduced pressure and used directly for the synthesis of the corresponding N-hydroxysulfonamide (1.9 g, 96% yield). ¹ H NMR (500 MHz, chloroform-d) δ 8.79 (1H, d, J 2.0Hz), 8.30 (1H, dd, 8.3, 2.0Hz), 7.74 (1H, d, 8.3Hz), 3.99 (3H, s).

Methyl 4-chloro-3- (hydroxysulfamoyl) benzoate Methyl 4-chloro-3- (hydroxysulfamoyl) benzoate is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide. , Synthesized from methyl 4-chloro-3- (chlorosulfonyl) benzoate (0.7 g, 2.6 mmol) (0.3 g, 45% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 10.05 (1H, br.s.), 9.90 (1H, s), 8.50 (1H, d, 2.1Hz), 8.18 (1H, dd, 8.4, 2.1Hz ), 7.85 (1H, d, 8.2 Hz), 3.90 (3H, s); predicted value [M−H] ⁻ = 2633.9733; observed value [M−H] ⁻ = 2633.973.

2-Fluoro-N-hydroxy-5-methylbenzene-1-sulfonamide (56)
2-Fluoro-N-hydroxy-5-methylbenzene-1-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide. Prepared from chloride (1 g, 4.8 mmol) (0.19 g, 20% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.71 (2H, s), 7.61 (1H, dd, 6.6, 1.7Hz), 7.54 (1H, dt, 8.2, 2.3Hz), 7.33 (1H, dd, 10.0, 8.6 Hz), 2.36 (3H, s); predicted value [M−H] ⁻ = 204.0131; observed value [M−H] ⁻ = 204.0121.

4-Chloro-N- (3-chloropropyl) -3- (hydroxysulfamoyl) -benzamide (57)
2-Chloro-5-[(3-chloropropyl) carbamoyl] benzene-1-sulfonyl chloride A solution of 4-chloro-3- (chlorosulfonyl) benzoyl chloride (1.5 g, 5.51 mmol) in chlorobenzene (20 mL). Was added azetidine hydrochloride (0.54 g, 5.79 mmol) and the reaction was heated to 130 ° C. for 18 hours, after which LC-MS showed no starting material remaining. The reaction mixture was concentrated under reduced pressure and triturated using diethyl ether to give the desired product as an off-white solid that was used directly in the synthesis of the corresponding N-hydroxysulfonamide (1 g 55% yield).

4-chloro-N- (3-chloropropyl) -3- (hydroxysulfamoyl) -benzamide 4-chloro-N- (3-chloropropyl) -3- (hydroxysulfamoyl) -benzamide is N- Prepared from 2-chloro-5-[(3-chloropropyl) carbamoyl] benzene-1-sulfonyl chloride (1 g, 3.4 mmol) according to the methods described herein for the synthesis of hydroxysulfonamide, diethyl Trituration with ether gave the desired compound as a white solid (0.13 g, 14% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.88 (1H, d, 2.7Hz), 9.81 (1H, d, 2.9Hz), 8.86 (1H, t, 5.4Hz), 8.45 (1H, d, 2.0 Hz), 8.11 (1H, dd, 8.4, 2.0Hz), 7.81 (1H, d, 8.4Hz), 3.70 (2H, t, 6.5Hz), 3.40 (2H, q, 6.5Hz), 1.91-2.06 (2H , m).

2-Chloro-N-hydroxy-5- [4- (hydroxyimino) piperidine-1-carbonyl] benzene-1-sulfonamide (58)
2-Chloro-5- (4-oxopiperidine-1-carbonyl) benzene-1-sulfonyl chloride of 4-chloro-3- (chlorosulfonyl) benzoyl chloride (1.0 g, 3.7 mmol) in chlorobenzene (15 mL) To the solution was added 4-piperidinone hydrochloride (0.59 g, 3.9 mmol) and the reaction was heated to 130 ° C. for 18 hours, after which LC-MS showed that no starting material remained. Indicated. The reaction mixture is concentrated under reduced pressure, taken up in DCM (50 mL), washed with water (2 × 10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the product, which is diluted with diethyl Trituration with ether gave the desired compound as an off-white solid (0.27 g, 22% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 7.96 (1H, d, 1.6Hz), 7.51-7.40 (2H, m), 3.74-3.56 (4H, m) 2.55-2.27 (4H, m).

2-chloro-N-hydroxy-5- [4- (hydroxyimino) piperidine-1-carbonyl] benzene-1-sulfonamide 2-chloro-N-hydroxy-5- [4- (hydroxyimino) piperidine-1- Carbonyl] benzene-1-sulfonamide is 2-chloro-5- (4-oxopiperidine-1-carbonyl) benzene-1-sulfonyl according to the methods described herein for the synthesis of N-hydroxysulfonamide. Synthesized from chloride (0.27 g, 0.82 mmol) and triturated with heptane: diethyl ether to give the desired compound as a white solid (0.05 g, 16% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.98 (1H, m), 9.86 (1H, m), 7.95 (1H, m), 7.71 (2H, m), 3.59 (2H, m), 3.29 ( 2H, m), 3.16 (2H, m), 2.95 (2H, m).

4-Chloro-3- (hydroxysulfamoyl) -N- (2-methoxyethyl) -N-methylbenzamide (59)
2-chloro-5-[(2-methoxyethyl) (methyl) carbamoyl] benzene-1-sulfonyl chloride 4-chloro-3- (chlorosulfonyl) benzoyl chloride (2.0 g, 3.7 mmol) in chlorobenzene (25 mL) ) Was added 2- (methoxyethyl) methylamine hydrochloride (0.48 g, 3.9 mmol) and the reaction was heated to 130 ° C. for 18 hours, after which LC-MS was Showed no remaining. The reaction mixture was concentrated under reduced pressure and used directly for the synthesis of the corresponding N-hydroxysulfonamide (2 g, 75% yield).

4-chloro-3- (hydroxysulfamoyl) -N- (2-methoxyethyl) -N-methylbenzamide 4-chloro-3- (hydroxysulfamoyl) -N- (2-methoxyethyl) -N- Methylbenzamide is prepared according to the method described herein for the synthesis of N-hydroxysulfonamide, 2-chloro-5-[(2-methoxyethyl) (methyl) carbamoyl] benzene-1-sulfonyl chloride (2 g, 6.1 mmol), triturated with diethyl ether and then eluted on a silica gel column eluted with ethyl acetate: heptane (1: 1 v: v) to give the desired compound as an off-white solid (0.17 g, 9% yield). Rate). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.98 (1H, m), 9.86 (1H, m), 7.95 (1H, m), 7.71 (2H, m), 3.59 (2H, m), 3.29 ( 2H, m), 3.16 (2H, m), 2.95 (3H, m).

2-Hydroxy-5- (hydroxysulfamoyl) benzoic acid (60)
2-Hydroxy-5- (hydroxysulfamoyl) benzoic acid is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide (5-g-chlorosulfonyl) -2-hydroxybenzoic acid (1 g, 4.2 mmol) and isolated as a white solid (0.4 g, 41% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 10.75 (1H, br.s.), 10.66 (1H, s), 9.39 (1H, d, 2.1Hz), 9.04 (1H, dd, 8.8, 2.2Hz ), 8.31 (1H, d, 5.0 Hz); predicted value [M−H] ⁻ = 231.9916; observed value [M−H] ⁻ = 2311.9907.

N-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide (61)
N-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide according to the method described herein. Prepared from methyl-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonyl chloride (0.9 g, 3.8 mmol) and triturated with heptane: ethyl acetate to give the desired product off-white. Obtained as a colored solid (0.35 g, 38% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.40 (1H, br.s.), 9.32 (1H, s), 7.00-7.12 (2H, m), 6.83 (1H, d, 8.9Hz), 4.20 -4.36 (2H, m), 3.24-3.35 (2H, m), 2.87 (3H, s); predicted value [M + H] ⁺ = 245.0595; observed value [M + H] ⁺ = 245.0589.

2-Chloro-N, 4-dihydroxybenzene-1-sulfonamide (62)
2-Chloro-4-hydroxybenzene-1-sulfonyl chloride A solution of 2-chloro-4-hydroxyaniline (5.0 g, 35 mmol) in acetic acid (30 mL) and HCl (7 mL) cooled to 0 ° C. was added to nitrous acid. Sodium (2.65 g, 38.5 mmol) was added in small portions while maintaining the internal temperature <5 ° C. The reaction mixture was stirred for 1 hour at 0 ° C. At the same time, CuCl ₂ .H ₂ O (5.98 g, 34.8 mmol) was suspended in AcOH: water (20 mL: 10 mL) at 0 ° C. and stirred at 0 ° C. until all the CuCl ₂ was dissolved. SO ₂ gas was condensed into the flask at −78 ° C. by using a cold finger, diazo compound and CuCl ₂ solution were added and the reaction was warmed to 0 ° C. The reaction was warmed to a temperature of about 25 ° C. over 18 hours, which was quenched by addition to ice and extracted into diethyl ether (3 × 100 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil that was used directly in the next step.

2-Chloro-N, 4-dihydroxybenzene-1-sulfonamide 2-Chloro-N, 4-dihydroxybenzene-1-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide. Prepared from 2-chloro-4-hydroxybenzene-1-sulfonyl chloride and chromatographed on a silica gel column eluted with 1% MeOH: DCM to give the desired compound as a white solid (0.3 g, 15% yield). ) Was obtained. ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 10.93 (1H, s), 9.58 (1H, d, 3.0Hz), 9.42 (1H, d, 3.0Hz), 7.80 (1H, d, 8.7Hz), 6.97 (1H, d, 2.4 Hz), 6.89 (1H, dd, 8.7, 2.4 Hz) Predicted value [M−H] ⁻ = 2211.9628; observed value [M−H] ⁻ = 2211.9621.

3,5-dichloro-N, 4-dihydroxybenzene-1-sulfonamide (63)
3,5-Dichloro-N, 4-dihydroxybenzene-1-sulfonamide is prepared according to the method described herein for the synthesis of N-hydroxysulfonamide. -Prepared from sulfonyl chloride (1 g, 3.8 mmol) to give the desired compound as a white solid (0.05 g, 5% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 9.60 (1H, br.s.), 9.43 (1H, s), 7.64 (2H, s).

4-Chloro-2-hydroxy-5- (hydroxysulfamoyl) -N, N-dimethylbenzamide (64)
2-Chloro-5- (dimethylcarbamoyl) -4-hydroxybenzene-1-sulfonyl chloride To a solution of 5- (chlorosulfonyl) -2-hydroxybenzoic acid (1 g, 4.2 mmol) in toluene (20 mL) was added chloride. Thionyl (0.62 mL, 8.4 mmol) was added and the reaction was heated to reflux for 1 hour or until no further starting material was seen by TLC. The reaction was concentrated under reduced pressure and used directly for amide synthesis (1 g, 82% yield). To a solution of 4-chloro-5- (chlorosulfonyl) -2-hydroxybenzoyl chloride (1 g, 3.5 mmol) in chlorobenzene (25 mL) was added dimethylamine hydrochloride (0.31 g, 3.9 mmol). The reaction was heated to 130 ° C. for 18 hours, after which LC-MS showed no starting material remained. The reaction mixture was concentrated under reduced pressure and used directly for the synthesis of the corresponding N-hydroxysulfonamide (2.9 g, quantitative yield); LC-MS t _R = 1.75 min, [M + H] ⁺ = H.264.

4-chloro-2-hydroxy-5- (hydroxysulfamoyl) -N, N-dimethylbenzamide 4-chloro-2-hydroxy-5- (hydroxysulfamoyl) -N, N-dimethylbenzamide is N- Prepared from 2-chloro-5- (dimethylcarbamoyl) -4-hydroxybenzene-1-sulfonyl chloride (2.9 g, 9.7 mmol) according to the method described herein for the synthesis of hydroxysulfonamide, Chromatography on a silica gel column eluted with 10% MeOH in DCM and then trituration from DCM gave the desired compound as an off-white solid (0.38 g, 13% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 11.42 (1H, br.s.), 9.67 (1H, d, 2.7Hz), 9.60 (1H, d, 2.9Hz), 7.68 (1H, s), 7.06 (1H, s), 2.96 (3H, br. S.), 2.81 (3H, br. S.); Predicted value [M−H] ⁻ = 292.9999; observed value [M−H] ⁻ = 293 .0003.

5-Chloro-N-hydroxy-1-methyl-2,3-dihydro-1H-indole-6-sulfonamide (65)
5-Chloro-1-methyl-2,3-dihydro-1H-indole To a solution of 5-chloro-2,3-dihydro-1H-indole (3.0 g, 19.5 mmol) in DMF (60 mL) was added dimethyl Carbonic acid (5.27 g, 58.6 mmol) and potassium carbonate (1.35 g, 9.75 mmol) were added. The reaction was heated to reflux for 18 hours, after which the starting material was not known by LC-MS. The reaction mixture was cooled to a temperature of about 25 ° C. and the product was isolated by extraction into diethyl ether (250 mL). The organic portion was washed with water (2 × 100 mL) and the organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid (2.4 g, 71% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 7.67 (1H, br.s.), 7.27 (1H, s), 7.20 (1H, d, 8.7Hz), 3.97 (2H, t, 8.7Hz), 3.74 (3H, br.s.), 3.09 (2H, t, 8.7Hz).

5-chloro-1-methyl-2,3-dihydro-1H-indole-6-sulfonyl chloride 5-chloro-1-methyl-2,3-dihydro-1H-indole (0.6 g, 3.6 mmol) and chloro Sulfonic acid (1.7 g, 14.3 mmol) was heated to 70 ° C. for 18 hours in a sealed tube. The reaction was quenched by pouring onto ice and the resulting solid was dried under reduced pressure and then chromatographed on a silica gel column eluted with 20% heptane: ethyl acetate to give the title compound as a white solid (0 .37 g, 38% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 8.23 (1H, br.s.), 7.19 (1H, s), 3.97 (2H, t, 8.7Hz), 3.75 (3H, s), 3.07 (2H , t, 8.6Hz).

5-chloro-N-hydroxy-1-methyl-2,3-dihydro-1H-indole-6-sulfonamide 5-chloro-N-hydroxy-1-methyl-2,3-dihydro-1H-indole-6 The sulfonamide was prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide, 5-chloro-1-methyl-2,3-dihydro-1H-indole-6-sulfonyl chloride (0.35 g, 1.3 mmol) (0.19 g, 55% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 9.54-9.72 (2H, m), 8.33 (1H, br.s.), 7.51 (1H, s), 4.03 (2H, t, 8.8Hz), 3.76 (3H, s), 3.18 (2H, t, 8.5Hz).

2-Chloro-N, 5-dihydroxybenzene-1-sulfonamide (66)
2-Chloro-N, 5-dihydroxybenzene-1-sulfonamide can be prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide (2-chloro-5-hydroxybenzene-1-sulfonyl chloride ( 2.32 g, 10 mmol) and chromatographed by neutral preparative reverse phase HPLC to give the desired compound as a white solid (0.05 g, 3% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 9.74 (2H, s), 7.31-7.53 (2H, m), 7.04 (1H, d, 8.7, 2.9 Hz).

5-Bromo-N-hydroxy-1-methyl-2,3-dihydro-1H-indole-6-sulfonamide (67)
5-Bromo-1-methyl-2,3-dihydro-1H-indole 5-Bromo-1-methyl-2,3-dihydro-1H-indole is 5-chloro-1-methyl-2,3-dihydro- Synthesized using the method described for the synthesis of 1H-indole (1.1 g, 54% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 7.60 (1H, br.s.), 7.40 (1H, d, 0.9Hz), 7.28-7.37 (1H, m), 3.96 (2H, t, 8.7Hz ), 3.74 (3H, s), 3.10 (2H, t, 8.7Hz).

5-Bromo-1-methyl-2,3-dihydro-1H-indole-6-sulfonyl chloride 5-Bromo-1-methyl-2,3-dihydro-1H-indole-6-sulfonyl chloride is 5-chloro- Synthesized using the method described for the synthesis of 1-methyl-2,3-dihydro-1H-indole-6-sulfonyl chloride (0.29 g, 34% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 8.30 (1H, br.s.), 7.37 (1H, s), 3.96 (2H, t, 8.7Hz), 3.74 (3H, br.s.), 3.07 (2H, t, 8.7Hz).

5-Bromo-N-hydroxy-1-methyl-2,3-dihydro-1H-indole-6-sulfonamide 5-Bromo-N-hydroxy-1-methyl-2,3-dihydro-1H-indole-6 The sulfonamide was prepared according to the method described herein for the synthesis of N-hydroxysulfonamide, bromo-1-methyl-2,3-dihydro-1H-indole-6-sulfonyl chloride (0.29 g,. 94 mmol) (0.24 g, 82% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 9.54-9.74 (2H, m), 8.38 (1H, br.s.), 7.68 (1H, s), 4.02 (2H, t, 8.7Hz), 3.76 (3H, s), 3.18 (2H, t, 8.6Hz).

2-Chloro-N-hydroxy-5- (methoxymethyl) benzene-1-sulfonamide (68)
1-Chloro-4- (methoxymethyl) -2-nitrobenzene 1-Chloro-4- (methoxymethyl) -2-nitrobenzene is synthesized according to Buenzli et al., J. Amer. Chem. Soc. 120: 12274-12288 (1998). ). To a solution of KOH (5.98 g, 106 mmol) in DMSO (50 mL) was added 4-chloro-3-nitrobenzyl alcohol (5.0 g, 26.6 mmol) and methyl iodide (4 mL, 64 mmol). Stirring was continued for 1 hour, after which water (60 mL) was added and the reaction was extracted into DCM (3 × 50 mL), washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure ( 4.7 g, 88% yield). ¹ H NMR (250 MHz, chloroform-d) δppm 7.86 (1H, d, 1.4Hz), 7.40-7.61 (2H, m), 4.49 (2H, s), 3.44 (3H, s).

2-Chloro-5- (methoxymethyl) benzene-1-sulfonyl chloride 1-chloro-4- (methoxymethyl) -2-nitrobenzene (2.7 g, 13.4 mmol) in EtOH (14 mL) and water (2 mL) To a solution of was added iron (1.94 g, 34.8 mmol) and HCl (5 drops). The reaction was heated to 80 ° C. for 1 hour. The cooled reaction mixture was filtered through celite, washed with EtOAc (50 mL), concentrated under reduced pressure and used directly in the next step. To a solution of 2-chloro-5- (methoxymethyl) aniline (4.19 g, 24.5 mmol) in acetic acid (25 mL) and HCl (6 mL) cooled to 0 ° C., sodium nitrite (1.85 g, 26.26). 9 mmol) was added in small portions while maintaining the internal temperature <5 ° C. The reaction mixture was stirred for 1 hour at 0 ° C. At the same time, CuCl ₂ .H ₂ O (4.16 g, 24.5 mmol) was suspended in AcOH: water (25 mL: 10 mL) at 0 ° C. and stirred at 0 ° C. until all the CuCl ₂ was dissolved. SO ₂ gas was condensed into the flask at −78 ° C. by using a cold finger, diazo compound and CuCl ₂ solution were added and the reaction was warmed to 0 ° C. The reaction was warmed to a temperature of about 25 ° C. over 2 hours. The reaction was quenched by adding to ice and extracted into DCM (3 × 50 mL). The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (5.1 g, 81% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 7.82 (1H, d, 2.0Hz), 7.30-7.48 (2H, m), 4.38 (2H, s), 3.27 (3H, s).

2-Chloro-N-hydroxy-5- (methoxymethyl) benzene-1-sulfonamide 1-Chloro-4- (methoxymethyl) -2-nitrobenzene is described herein for the synthesis of N-hydroxysulfonamide. Prepared from 2-chloro-5- (methoxymethyl) benzene-1-sulfonyl chloride (1 g, 3.9 mmol) according to the method described (0.55 g, 56% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 9.69-9.89 (2H, m), 7.93 (1H, d, 1.7Hz), 7.68 (1H, d, 8.1Hz), 7.60 (1H, dd, 8.2, 2.0Hz), 4.49 (2H, s), 3.33 (3H, s); predicted value [M−H] ⁻ = 249.9994; observed value [M−H] ⁻ = 249.9945.

Methyl 5- (hydroxysulfamoyl) furan-2-carboxylate (69)
Methyl 5- (hydroxysulfamoyl) furan-2-carboxylate is prepared according to the method described herein for the synthesis of N-hydroxysulfonamide, methyl 5- (chlorosulfonyl) furan-2-carboxylate ( 1.0 g, 4.5 mmol) and chromatographed on a silica gel column eluted with heptane: ethyl acetate (4: 1 v: v) and then triturated from heptane to give the desired compound as a yellow solid (0. 46 g, 47% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 10.28 (1H, d, 2.8Hz), 9.89 (1H, d, 2.8Hz), 7.48 (1H, d, 3.8Hz), 7.36 (1H, d, 3.6 Hz), 3.87 (3H, s).

N-hydroxy-2,5-dimethylfuran-3-sulfonamide (70)
N-hydroxy-2,5-dimethylfuran-3-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide (2,5-dimethylfuran-3-sulfonyl chloride (0. 5g, 2.6mmol) and triturated with DCM: heptane to give the desired compound as a white solid (0.34g, 69% yield). ¹ H NMR (CDCl ₃ , 500 MHz) δppm 6.65 (1H, d, 3.7 Hz), 6.20 (1H, s), 6.13 (1H, s), 2.54 (3H, s), 2.28 (3H, s).

N-hydroxy-8-oxatricyclo [7.4.0.0] trideca-1 (9), 2 (7), 3,5,10,12-hexaene-4-sulfonamide (71)
N-hydroxy-8-oxatricyclo [7.4.0.0] trideca-1 (9), 2 (7), 3,5,10,12-hexaene-4-sulfonamide is N-hydroxysulfone according to the methods described herein for the synthesis of amides, 8-oxatricyclo [7.4.0.0 ^{2, 7]} trideca-1 (9), 2,4,6,10,12- hexaene Synthesized from -4-sulfonyl chloride (1.0 g, 3.75 mmol) and triturated with diethyl ether to give the desired compound as a white solid (0.46 g, 48% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.66 (1H, d, 3.3Hz), 9.62 (1H, d, 3.3Hz), 8.67 (1H, d, 1.7Hz), 8.35 (1H, d, 7.7 Hz), 7.93-8.02 (2H, m), 7.80 (1H, d, 8.4Hz), 7.58-7.65 (1H, m), 7.49 (1H, t, 7.5Hz).

2- (ethanesulfonyl) -N-hydroxybenzene-1-sulfonamide (72)
1-chloro-2- (ethylsulfanyl) benzene To a solution of sodium methoxide (5.6 g, 103.7 mmol) in MeOH (100 mL) was added 2-chlorobenzene-1-thiol (10.0 g in MeOH (50 mL)). 69.1 mmol). The reaction was cooled to 0 ° C. and a solution of iodoethane (5.8 mL, 72.6 mmol) in MeOH (50 mL) was added dropwise. The reaction was stirred at a temperature of about 25 ° C. for 18 hours, at which time LC-MS showed no starting material present. The reaction was quenched by removing the solvent and adding water (100 mL). The organics were extracted and combined into DCM (3 × 200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired compound as a turbid oil (11.5 g, 96% yield). It was. ¹ H NMR (CDCl ₃ , 500 MHz) δppm 7.36 (1H, dd, 7.9, 1.2Hz), 7.28-7.19 (2H, m), 7.13-7.07 (1H, m), 2.97 (2H, q, 7.4Hz) , 1.37 (3H, t, 7.4Hz).

1-chloro-2- (ethanesulfonyl) benzene To a 0-5 ° C. solution of 10% sulfuric acid (345 mL), 1-chloro-2- (ethylsulfanyl) benzene (11.5 g, 66.6) in DCM (230 mL). 6 mmol) was added over 1 hour with simultaneous addition of potassium permanganate solid (35.8 g, 0.23 mol) in small portions. The resulting reaction mixture was warmed to a temperature of about 25 ° C. and stirring was continued for 1 hour, after which LC-MS showed that the reaction was complete. Sodium bisulfite (65 g) was slowly added to the reaction mixture until all of the color disappeared from the reaction and a clear, colorless solution was observed and the organic phase was separated. The aqueous phase is re-extracted into DCM (3 × 100 mL) and the combined organic portions are dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired compound as a clear, colorless oil. Used directly in next step (14.0 g, 99.99% yield). ¹ H NMR (CDCl ₃ , 500 MHz) δppm 8.13 (1H, dd, 8.0, 1.1Hz), 7.62-7.54 (2H, m), 7.48 (1H, ddd, 8.6, 6.6, 2.1Hz), 3.44 (2H, q, 7.5Hz), 1.27 (3H, t, 7.5Hz).

1- (Benzylsulfanyl) -2- (ethanesulfonyl) benzene To a solution of 1-chloro-2- (ethanesulfonyl) benzene (14.0 g, 68.4 mmol) in DMSO (70 mL) was added (benzylsulfanyl) methaneimide. Amide HCl (14.56 g, 71.8 mmol) was added and the reaction mixture was cooled to 10 ° C. To the reaction mixture was added NaOH (6.84 g, 171.0 mmol) and the reaction was heated to 75 ° C. for 18 hours, cooled to a temperature of about 25 ° C. and stirring was continued for an additional 72 hours. The reaction was quenched by adding water (50 mL) and the resulting aqueous solution was extracted into DCM (4 × 100 mL). The combined organics were washed with brine solution (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product as a yellow oil which was gradient from 50-100% DCM acetate: heptane. Chromatography on a silica gel column eluted with gave the desired compound as a yellow oil (3.25 g, 16% yield). ¹ H NMR (CDCl ₃ , 500 MHz) δppm 8.06-8.00 (1H, m), 7.54-7.45 (2H, m), 7.35 (1H, ddd, 8.5, 6.8, 1.9Hz), 7.32-7.21 (5H, m ), 4.23 (2H, s), 3.37 (2H, d, 7.4Hz), 1.11 (3H, t, 7.4Hz).

2- (ethanesulfonyl) benzene-1-sulfonyl chloride through a solution of 1- (benzylsulfanyl) -2- (ethanesulfonyl) benzene (3.25 g, 11.1 mmol) in acetic acid (110 mL) and water (10 mL) Chlorine gas was bubbled for 1 hour while maintaining the internal temperature <10 ° C. Upon complete addition of chlorine gas, the sulfonyl chloride was extracted into DCM (100 mL) and washed with water (100 mL) and 2.5% w: v NaOH solution (50 mL). The organic portion was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was triturated with heptane to give the desired compound as a white solid (2.7 g, 89% yield). ¹ H NMR (CDCl ₃ , 500 MHz) δppm 8.44 (1H, dd, 7.8, 1.3 Hz), 8.40 (1H, dd, 7.7, 1.4 Hz), 7.97 (2H, dtd, 22.4, 7.6, 1.3 Hz), 3.61 (2H, q, 7.5Hz), 1.36 (3H, t, 7.5Hz).

2- (ethanesulfonyl) -N-hydroxybenzene-1-sulfonamide 2- (ethanesulfonyl) -N-hydroxybenzene-1-sulfonamide is described herein for the synthesis of N-hydroxysulfonamide According to the method, synthesized from 2- (ethanesulfonyl) benzene-1-sulfonyl chloride (1.0 g, 3.7 mmol) and triturated with heptane to give the desired compound as a white solid (0.8 g, 83% yield) As obtained. ¹ H NMR (DMSO, 500 MHz) δppm 10.12 (1H, d, 3.5Hz), 8.96 (1H, d, 3.5Hz), 8.26-8.19 (2H, m), 8.08-7.99 (2H, m), 3.65 ( 2H, q, 7.4Hz), 1.17 (3H, t, 7.4Hz).

N-hydroxy-2- (propane-2-sulfonyl) benzene-1-sulfonamide (73)
1-chloro-2- (propan-2-ylsulfanyl) benzene A solution of sodium methoxide (5.6 g, 103.7 mmol) in MeOH (100 mL) was added to 2-chlorobenzene-1-thiol in MeOH (50 mL). (10.0 g, 69.1 mmol) was added. The reaction was cooled to 0 ° C. and a solution of 2-iodopropane (7.26 mL, 72.6 mmol) in MeOH (50 mL) was added dropwise. The reaction was stirred at a temperature of about 25 ° C. for 18 hours, at which point LC-MS showed that starting material was still present. An additional portion of 2-iodopropane (3 mL, 30 mmol) and sodium methoxide (3 g, 29 mmol) was added and stirring was continued for another 18 hours until complete consumption of starting material was observed by LC-MS. The reaction was quenched by removing the solvent and adding water (100 mL). The organics were extracted and combined into DCM (3 × 200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired compound as a turbid oil (12.8 g, 99% yield). It was. ¹ H NMR (CDCl ₃ , 500 MHz) δppm 7.39 (2H, d, 7.9Hz), 7.21 (1H, td, 7.6, 1.4Hz), 7.14 (1H, td, 7.7, 1.6Hz), 3.50 (1H, heptad Line, 6.7Hz), 1.34 (6H, d, 6.7Hz).

1-chloro-2- (propane-2-sulfonyl) benzene 1-chloro-2- (propan-2-ylsulfanyl) benzene in DCM (230 mL) in a 0-5 ° C. solution of 10% sulfuric acid (380 mL) A solution of (12.8 g, 68.3 mmol) was added over 1 hour with simultaneous addition of potassium permanganate solid (36.7 g, 0.23 mol) in small portions. The resulting reaction mixture was warmed to a temperature of about 25 ° C. and stirring was continued for 1 hour, after which LC-MS showed that the reaction was complete. Sodium bisulfite (60 g) was added slowly to the reaction mixture until all of the color disappeared from the reaction and a clear, colorless solution was observed, and the organic phase was separated. The aqueous phase was re-extracted into DCM (3 × 100 mL) and the combined organic portions were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired compound as a clear, colorless oil (13.7 g, 92% yield). ¹ H NMR (CDCl ₃ , 250 MHz) δppm 8.17-8.06 (1H, m), 7.62-7.52 (2H, m), 7.46 (1H, ddd, 8.7, 5.5, 3.2Hz), 3.80 (1H, triplet, 6.9Hz), 1.32 (6H, dd, 6.9, 0.9Hz).

1- (Benzylsulfanyl) -2- (propane-2-sulfonyl) benzene To a solution of 1-chloro-2- (propane-2-sulfonyl) benzene (13.7 g, 62.6 mmol) in DMSO (70 mL), (Benzylsulfanyl) methanimidamide HCl (13.3 g, 65.8 mmol) was added and the reaction mixture was cooled to 10 ° C. To the reaction mixture was added NaOH (6.3 g, 156.6 mmol) and the reaction was heated to 75 ° C. for 18 hours. The reaction was quenched by the addition of water (50 mL) and the resulting aqueous solution was extracted into DCM (4 × 100 mL). The combined organics were washed with brine solution (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the product as a yellow oil which was gradient from 50-100% DCM acetate: heptane. Chromatography on a silica gel column eluted with gave the desired compound as a yellow oil (4.7 g, 20% yield). ¹ H NMR (CDCl ₃ , 500 MHz) δppm 8.03-7.98 (1H, m), 7.50-7.45 (2H, m), 7.36-7.21 (6H, m), 4.23 (2H, s), 3.82 (1H, dt , 13.7, 6.9Hz), 1.19 (6H, d, 6.9Hz).

2- (propane-2-sulfonyl) benzene-1-sulfonyl chloride 1- (benzylsulfanyl) -2- (propane-2-sulfonyl) benzene (4.1 g, 13. mL) in acetic acid (140 mL) and water (12 mL). 4 mmol), chlorine gas was bubbled for 1 hour while maintaining the internal temperature at <10 ° C. Upon complete addition of chlorine gas, the sulfonyl chloride was extracted into DCM (100 mL) and washed with water (100 mL) and 2.5% w: v NaOH solution (50 mL). The organic portion was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was triturated with heptane to give the desired compound as a white solid (2.9 g, 77% yield). ¹ H NMR (CDCl ₃ , 500 MHz) δppm 8.42 (1H, dd, 7.8, 1.4Hz), 8.34 (1H, dd, 7.6, 1.6Hz), 7.93 (2H, dtd, 20.1, 7.5, 1.4Hz), 4.05 (1H, 7-wire, 6.8Hz), 1.35 (6H, d, 6.9Hz).

N-hydroxy-2- (propane-2-sulfonyl) benzene-1-sulfonamide N-hydroxy-2- (propane-2-sulfonyl) benzene-1-sulfonamide is described herein for the synthesis of N-hydroxysulfonamide. Prepared from 2- (propane-2-sulfonyl) benzene-1-sulfonyl chloride (1.0 g, 3.5 mmol) and triturated with heptane following the method described in the 0.84 g, 85% yield). ¹ H NMR (DMSO, 500 MHz) δppm 10.11 (1H, d, 3.5Hz), 8.93 (1H, d, 3.5Hz), 8.26-8.22 (1H, m), 8.22-8.17 (1H, m), 8.06- 7.99 (2H, m), 4.09 (1H, heptad, 6.9Hz), 1.22 (6H, d, 6.8Hz).

4-acetyl-N-hydroxy-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide (74)
4-acetyl-N-hydroxy-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide according to the method described herein. Prepared from acetyl-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonyl chloride (0.72 g, 2.6 mmol) and triturated with diethyl ether to give the desired compound as a white solid (0. 0. 70 g, 59% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.50 (1H, br.s.), 9.43 (1H, br.s.), 7.47 (1H, d, 8.4Hz), 7.09 (1H, d, 8.5 Hz), 4.36 (2H, t, 4.3Hz), 3.89 (2H, t, 4.4Hz), 2.27 (3H, s).

Methyl 5- (hydroxysulfamoyl) -1-methyl-1H-pyrrole-2-carboxylate (75)
Methyl 5- (hydroxysulfamoyl) -1-methyl-1H-pyrrole-2-carboxylate is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide. Prepared from -1-methyl-1H-pyrrole-2-carboxylate (0.46 g, 1.9 mmol) and triturated with diethyl ether to give the desired compound as a white solid (0.09 g, 19% yield). Obtained. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.47 (1H, d, 3.3Hz), 9.21 (1H, d, 3.5Hz), 7.70 (1H, d, 1.6Hz), 7.06 (1H, d, 1.9 Hz), 3.91 (3H, s), 3.78 (3H, s).

N- [5- (hydroxysulfamoyl) -1,3-thiazol-2-yl] acetamide (76)
N- [5- (hydroxysulfamoyl) -1,3-thiazol-2-yl] acetamide is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide, 2- (acetylamino) Prepared from -1,3-thiazole-5-sulfonyl chloride (0.28 g, 1.3 mmol) and triturated with diethyl ether to give the desired compound as a white solid (0.12 g, 42% yield). It was. ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.80 (1H, d, 3.2Hz), 9.65 (1H, d, 3.3Hz), 7.94 (1H, s), 2.20 (3H, s).

N-hydroxy-2,5-dimethyl-4- (morpholine-4-carbonyl) furan-3-sulfonamide (77)
4- (2,5-Dimethylfuran-3-carbonyl) morpholine A solution of diisopropylethylamine (3.8 mL, 21.5 mmol) and morpholine (1.79 g, 20.5 mmol) in DCM (30 mL) cooled to 0 ° C. 2,5 dimethyl-furan-3-carbonyl chloride (3.1 g, 19.6 mmol) was added and the resulting solution was warmed to a temperature of about 25 ° C. for 6 hours. The reaction was quenched by the addition of 1N HCl (20 mL) and the organic portion was extracted into DCM (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired compound as a brown oil. (4.41 g, quantitative yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 6.09 (1H, s), 3.40-3.63 (8H, m), 2.25 (3H, s), 2.21 (3H, s).

2,5-Dimethyl-4- (morpholine-4-carbonyl) furan-3-sulfonyl chloride To chlorosulfonic acid (6.4 mL, 95 mmol), 4- (2,5-dimethylfuran-3-carbonyl) morpholine (2. 0 g, 9.6 mmol) was added and the reaction was heated to 90 ° C. for 1 h, after which LC-MS showed complete consumption of starting material. The brown solution is poured onto ice and the organic portion is extracted into DCM (2 × 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired compound as a brown solid, which corresponds to the corresponding Used directly in the synthesis of N-hydroxysulfonamide (2.29 g, 78% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 3.03-3.85 (8H, m), 2.31 (3H, s), 2.07 (3H, s).

N-hydroxy-2,5-dimethyl-4- (morpholine-4-carbonyl) furan-3-sulfonamide N-hydroxy-2,5-dimethyl-4- (morpholine-4-carbonyl) furan-3-sulfonamide Is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide, 2,5-dimethyl-4- (morpholine-4-carbonyl) furan-3-sulfonyl chloride (2.3 g, 7.4 mmol). ) And triturated with DCM to give the desired compound as an off-white solid (1.3 g, 56% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.71 (1H, d, 3.5Hz), 8.64 (1H, d, 3.6Hz), 3.62-3.78 (2H, m), 3.42 -3.62 (4H, m) , 3.36-3.42 (2H, m), 2.47 (3H, s), 2.22 (3H, s).

Ethyl 5- (hydroxysulfamoyl) furan-3-carboxylate (78)
Ethyl 5- (hydroxysulfamoyl) furan-3-carboxylate is prepared according to the methods described herein for the synthesis of N-hydroxysulfonamide, ethyl 5- (chlorosulfonyl) furan-3-carboxylate ( 0.3g, 1.4mmol) and triturated with heptane to give the desired compound as an off-white solid (0.2g, 60% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 10.14 (1H, br.s.), 9.88 (1H, s), 8.76 (1H, d, 0.8Hz), 7.38 (1H, d, 0.8Hz), 4.28 (2H, q, 7.1Hz), 1.21-1.35 (3H, t, 7.1Hz).

5-Chlorothiophene-2-sulfonamidooxane-4-carboxylate (79)
[(Tert-Butoxy) carbonyl] aminooxane-4-carboxylate To a solution of tetrahydro-2H-pyran-4-carboxylic acid (5.0 g, 38.42 mmol) in DCM (200 mL) was added EDCI (5.96 g, 38 .42 mmol) was added. The reaction was stirred at a temperature of about 25 ° C. for 10 minutes, BOC hydroxylamine (5.12 g, 38.42 mmol) was added and stirring was continued for 18 hours. The reaction mixture is diluted with DCM (50 mL), washed with water (2 × 20 mL) and brine (1 × 20 mL), dried over magnesium sulfate, filtered and concentrated to [(tert-butoxy) carbonyl] aminooxane. -4-carboxylate was obtained as a light orange oil (6.93 g, 74% yield). ¹ H NMR (250 MHz, chloroform-d) δppm 8.00 (1H, br.s.), 3.98 (2H, td, 3.7, 11.7Hz), 3.60-3.32 (2H, m), 2.86-2.64 (1H, m ), 1.79 (4H, s), 1.48 (9H, s).

N-[(tert-Butoxy) carbonyl] 5-chlorothiophene-2-sulfonamidooxane-4-carboxylate [(tert-Butoxy) carbonyl] aminooxane-4-carboxylate (2 g, 8 in DCM (100 mL)) To a solution of .15 mmol) was added 5-chlorothiophene-2-sulfonyl chloride (1.09 mL, 8.15 mmol) and triethylamine (1.7 mL, 12.23 mmol), followed by DMAP (149 mg, 1.22 mmol) did. The reaction mixture was stirred at a temperature of about 25 ° C. for 1 hour and then water (10 mL) was added. The mixture is shaken, the two layers are separated, and the organic layer is washed with aqueous 0.1 M HCl (1 × 10 mL), water (1 × 10 mL) and brine (1 × 10 mL) and dried over magnesium sulfate. Filtered and concentrated under reduced pressure to give an oil. The product was chromatographed on a silica gel column eluted with heptane: EtOAc 30% to 40% to give N-[(tert-butoxy) carbonyl] 5-chlorothiophene-2-sulfonamidooxane-4-carboxylate ( 0.92 g, 27% yield). ¹ H NMR (500 MHz, chloroform-d) δppm 7.65 (1H, d, 4.3Hz), 7.00 (1H, d, 4.1Hz), 4.01 (2H, td, 3.6, 11.7Hz), 3.55-3.46 (2H, m), 2.84 (1H, tt, 5.1, 9.8Hz), 2.00-1.87 (4H, m), 1.49 (9H, s).

5-Chlorothiophene-2-sulfonamidooxane-4-carboxylate N-[(tert-butoxy) carbonyl] 5-chlorothiophene-2-sulfonamidooxane-4-carboxylate in DCM (8 mL) (0 To a solution of .86 g, 2.0 mmol) was added trifluoroacetic acid (2.24 mL, 30.3 mmol) and the reaction mixture was stirred at a temperature of about 25 ° C. for 1 hour. Evaporation of the solvent yielded a yellow oil which was chromatographed on a silica gel column eluted with heptane: EtOAc 20% to 50% to give 5-chlorothiophene-2-sulfonamidooxane-4-carboxylate. Was obtained as a white solid (0.53 g, 80% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 11.52 (1H, br.s.), 7.68 (1H, d, 4.1Hz), 7.39 (1H, d, 4.1Hz), 3.80 (2H, td, 3.5 , 11.3Hz), 3.41-3.30 (2H, m), 2.78 (1H, tt, 4.1, 11.1Hz), 1.73 (2H, dd, 2.1, 12.8Hz), 1.62-1.49 (2H, m).

N-hydroxy-2- (oxan-4-ylmethanesulfonyl) benzene-1-sulfonamide (80)
4-[(2-Fluorobenzenesulfonyl) methyl] oxane 4- (iodomethyl) oxane (1.0 g, 4.4 mmol) and 2-fluorobenzene-1-thiol (0.57 g, 4.3) in DMF (10 mL). 4 mmol) was added potassium carbonate (0.79 g, 5.7 mmol) and the reaction mixture was stirred at a temperature of about 25 ° C. for 18 hours. The reaction was quenched by adding water (20 mL) and the organic portion was extracted into DCM (50 mL). The organic material was washed with water (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was chromatographed on a silica gel column eluted with 100-70% heptane: ethyl acetate to give the desired compound as a clear, colorless oil (0.9 g, 92% yield). ¹ H NMR (500 MHz, chloroform-d) δppm 7.37 (1H, td, 7.6, 1.7Hz), 7.18-7.25 (1H, m), 6.99-7.17 (2H, m), 3.85-4.04 (2H, m) , 3.35 (2H, td, 11.8, 2.0Hz), 2.84 (2H, d, 6.9Hz), 1.77-1.87 (2H, m), 1.65-1.77 (1H, m), 1.36 (2H, qd, 12.3, 4.4 Hz).

4-{[2- (Benzylsulfanyl) benzenesulfonyl] methyl} oxane To a solution of 4-[(2-fluorobenzenesulfonyl) methyl] oxane (1.0 g, 3.9 mmol) in DMSO (20 mL) was added benzylcarbamate. The mixture was cooled while adding muimidothioate hydrochloride (0.84 g, 4.2 mmol) and NaOH (0.4 g, 9.8 mmol) was added and the internal temperature was between 15 ° C. and less than 20 ° C. To keep. The reaction mixture is heated at 75 ° C. for 2 hours, after which LC-MS shows complete consumption of starting material. The reaction was cooled to a temperature of about 25 ° C. and quenched by adding 1N HCl solution (5 mL). The formed emulsion was extracted with ethyl acetate (2 × 50 mL), and the resulting organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The oil was chromatographed on a silica gel column eluted with 20-40% heptane: ethyl acetate to give the desired compound as a yellow oil (1.2 g, 87% yield). ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 7.78-7.95 (2H, m), 7.67 (1H, td, 7.7, 1.5Hz), 7.14-7.49 (6H, m), 4.40 (2H, s), 3.71 (2H, dt, 9.7, 1.9Hz), 3.30 (2H, d, 6.4Hz), 3.17 (2H, td, 11.6, 2.1Hz), 1.79-1.97 (1H, m), 1.48 (2H, dd, 13.0 , 1.9Hz), 1.06-1.30 (2H, m).

2-([Oxan-4-ylmethanesulfonyl) benzene-1-sulfonyl chloride 4-{[2- (benzylsulfanyl) benzenesulfonyl] methyl} oxane (1 g, 2.8 mmol) in acetic acid (35 mL) and water (3 mL) ) Was bubbled through the solution for 1 hour while maintaining the internal temperature <10 ° C. Upon complete addition of chlorine gas, the sulfonyl chloride was extracted into DCM (150 mL) and washed with water (150 mL) and 2.5% w: v NaOH solution (50 mL). The organic portion is dried over sodium sulfate, filtered, concentrated under reduced pressure, and chromatographed on a silica gel column eluted with 80% ethyl acetate: heptane to give the desired compound as an oil which corresponds to the corresponding Used directly in the synthesis of N-hydroxysulfonamide (0.9 g, 96% yield). ¹ H NMR (500 MHz, chloroform-d) δppm 8.40 (2H, ddd, 7.6, 5.9, 1.4 Hz), 7.88-8.05 (2H, m), 3.87-4.03 (2H, m), 3.38-3.51 (3H, m), 2.99 (1H, br.s.), 2.41-2.64 (1H, m), 1.80-1.91 (2H, m), 1.43-1.63 (2H, m).

N-hydroxy-2- (oxan-4-ylmethanesulfonyl) benzene-1-sulfonamide N-hydroxy-2- (oxan-4-ylmethanesulfonyl) benzene-1-sulfonamide is a derivative of N-hydroxysulfonamide. Prepared from 2- (oxan-4-ylmethanesulfonyl) benzene-1-sulfonyl chloride (0.72 g, 2.1 mmol) according to the methods described herein for synthesis and prepared from heptane: ethyl acetate (1: Chromatography on a silica gel column eluted with 1 v: v) gave the desired compound as a white solid (0.37 g, 52% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 10.11 (1H, d, 3.5Hz), 8.98 (1H, d, 3.5Hz), 8.23-8.28 (1H, m), 8.17-8.22 (1H, m) , 7.99-8.04 (2H, m), 3.74-3.81 (2H, m), 3.62 (2H, d, 6.5Hz), 3.29 (2H, td, 11.6, 2.0Hz), 2.11-2.23 (1H, m), 1.66 (2H, dd, 13.1, 1.9Hz), 1.28-1.40 (2H, m).

N-hydroxy-3-methyl-1-benzofuran-2-sulfonamide (81)
Ethyl 2- (2-acetylphenoxy) acetate A solution of 1- (2-hydroxyphenyl) ethan-1-one (7.5 g, 0.06 mol) in dimethylformamide (75 mL) at a temperature of about 25 ° C. (22.8 g, 0.17 mol) was added. After stirring the reaction mixture for 10 minutes, ethyl bromoacetate (9.2 mL, 0.08 mol) was added and stirring was continued at a temperature of about 25 ° C. for an additional 5 hours. After completion of the reaction observed by TLC, the reaction was diluted with ethyl acetate (150 mL) and water (150 mL), the organic portion was separated and the aqueous portion was further extracted with ethyl acetate (2 × 150 mL). The combined organic layers were washed with water (2 × 150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the O-alkylated product as a colorless oil. The product was chromatographed on a silica gel column eluted with 5-8% ethyl acetate: hexane to give ethyl 2- (2-acetylphenoxy) acetate as an off-white solid (10.5 g, 86% yield). Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δppm 7.78-7.74 (1H, m), 7.47-7.41 (1H, m), 7.08-7.02 (1H, m), 6.85-6.80 (1H, m), 4.72 (2H , s), 4.28 (2H, q, 7.1Hz), 2.72 (3H, s), 1.30 (3H, t, 7.1Hz).

2- (2-acetylphenoxy) acetic acid To a solution of ethyl 2- (2-acetylphenoxy) acetate (8 g, 0.04 mol) in ethanol: water (80 mL: 8 mL) at 0 ° C. with lithium hydroxide hydrate ( 1: 1: 1) (4.5 g, 0.11 mol) was added. The reaction mixture was stirred at a temperature of about 25 ° C. for 18 hours and after completion of the reaction (observed by TLC), the reaction mixture was concentrated under reduced pressure. The product was taken up in water (350 mL) and extracted with diethyl ether (2 × 150 mL). The aqueous extract was then acidified with 1N HCl (pH about 2-3) at 0 ° C. and extracted into dichloromethane (4 × 300 mL). The combined organic layers were washed with water (150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the acid product as an off-white solid. Trituration with pentane gave the product, the compound, as an off-white solid (6.7 g, 95.8% yield). ¹ H NMR (400 MHz, DMSO) δppm 13.16 (1H, s), 7.60-7.55 (1H, m), 7.54-7.49 (1H, m), 7.12-7.07 (1H, m), 7.07-7.02 (1H, m), 4.85 (2H, s), 2.62 (3H, s).

To a solution of 2- (2-acetylphenoxy) acetic acid (8 g, 0.041 mol) in 3-methyl-1-benzofuran acetic anhydride (48 mL) at a temperature of about 25 ° C., sodium acetate (20.3 g, 0.25 mol) Was added. The reaction mixture was stirred at reflux (140 ° C.) for 18 hours. When the reaction was complete (checked by TLC), the reaction mixture was poured into ice cold water (400 mL) and extracted into ethyl acetate (3 × 400 mL). The combined organic layers were washed with water (400 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the cyclized product as a red oil that was chromatographed on a silica gel column eluted with hexane. Upon chromatography, the cyclized compound was obtained as a colorless liquid (2.6 g, 48% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δppm 7.55-7.51 (1H, m), 7.48-7.44 (1H, m), 7.42-7.39 (1H, m), 7.32-7.27 (1H, m), 7.27-7.22 (1H, m), 2.26 (3H, d, 1.3Hz).

3-Methyl-1-benzofuran-2-sulfonyl chloride—To a solution of 3-methyl-1-benzofuran (2.6 g, 17.7 mmol) in diethyl ether (50 mL) cooled to 78 ° C. was added n-BuLi (hexane). 2.5M solution in 8.7 mL, 21.64 mmol) was added dropwise. After stirring the reaction for 1 hour, SO ₂ gas was bubbled through the reaction and stirring was continued for an additional hour at −50 ° C. The reaction was warmed to −20 ° C., NCS (3.42 g, 25.58 mmol) was added in portions and stirring was continued at a temperature of about 25 ° C. for 18 hours. After substantially complete consumption of the starting material was observed by TLC, water (40 mL) was added and the organic portion was extracted into ethyl acetate (3 × 20 mL), dried over sodium sulfate and filtered, under reduced pressure Concentrated. The product was chromatographed on a silica gel column eluted with 0.5% ethyl acetate in hexanes to give the desired compound as a yellow solid (2.5 g, 55% yield). ¹ H NMR (300 MHz, CDCl ₃ ) δppm 7.72 (1H, dd, 7.9, 0.9Hz), 7.64-7.58 (2H, m), 7.43 (1H, dd, 8.1, 4.2Hz), 2.65 (3H, s) .

N-hydroxy-3-methyl-1-benzofuran-2-sulfonamide N-hydroxy-3-methyl-1-benzofuran-2-sulfonamide is described herein for the synthesis of N-hydroxysulfonamide. Prepared from 3-methyl-1-benzofuran-2-sulfonyl chloride (1.5 g, 6.5 mmol) according to method and triturated with 5% DCM: pentane to give the desired compound as a white solid (0.74 g, 50 % Yield). ¹ H NMR (400 MHz, DMSO) δppm 10.11 (1H, d, 3.0Hz), 9.79 (1H, d, 3.0Hz), 7.81 (1H, ddd, 7.9, 1.1, 0.7Hz), 7.70-7.66 (1H, m), 7.55 (1H, ddd, 8.4, 7.2, 1.3Hz), 7.41 (1H, td, 7.6, 0.9Hz), 2.50 (3H, s).

N-hydroxy-5- (piperidine-1-carbonyl) furan-2-sulfonamide (82)
5- (piperidine-1-carbonyl) furan-2-sulfonyl chloride In a sealed tube, sulfur trioxide pyridine complex (2.66 g, 16.74 mmol) and 1,2 dichloroethane (20 mL) were added to (furan-2-carbonyl). Heated with piperidine (2 g, 11.16 mmol) at 140 ° C. for 22 hours, then the reaction mixture was cooled to a temperature of about 25 ° C. and the mixture was concentrated under reduced pressure to give a slurry. The residue was treated with aqueous sodium carbonate (1.7 g, 16.74 mmol) (20 mL) and the resulting mixture was evaporated to dryness. The solid was stirred with dichloromethane (20 mL) and then refluxed in ethanol (10 mL) for 30 minutes, and the filtrate was concentrated under reduced pressure to give 1.2 g of sodium salt. This sodium salt was dissolved in methanol (10 mL), and the resulting solution was treated with activated carbon and filtered through celite. The filtrate was concentrated under reduced pressure to give 5- (piperidine-1-carbonyl) furan-2-sulfonic acid as a sodium salt (950 mg). This sodium salt was mixed with dichloromethane (10 mL) at 0 ° C. and slowly added to phosphorus oxychloride (2 mL). To this reaction mixture was then added phosphorous pentachloride (2.32 g, 16.74 mmol) in portions at 0 ° C. and the reaction mixture was warmed to a temperature of about 25 ° C. and stirred at this temperature for an additional 2 hours. The reaction mixture is diluted with dichloromethane (30 mL) and water (20 mL), the organic portion is separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5- (piperidine-1-carbonyl) furan- 2-sulfonyl chloride (0.6 g, 19% yield) was obtained.

N-hydroxy-5- (piperidine-1-carbonyl) furan-2-sulfonamide Aqueous hydroxylamine in tetrahydrofuran (7 mL) and water (3 mL) cooled to -5 ° C. (0.3 mL of 50% aqueous solution, 4.95 mmol) ) Was slowly added to a solution of 5- (piperidine-1-carbonyl) furan-2-sulfonyl chloride (550 mg, 1.98 mmol) in THF (3 mL) while maintaining the reaction temperature below 10 ° C. It was. The reaction is maintained at this temperature until substantially complete consumption of the sulfonyl chloride is observed by TLC (about 30 minutes), after which the reaction is diluted with dichloromethane (20 mL) and the organic portion is separated. Wash with water (2 × 10 mL), dehydrate with sodium sulfate, filter, and concentrate under reduced pressure to give N-hydroxy-5- (piperidine-1-carbonyl) furan-2-sulfonamide as a yellow solid. It was. Trituration with DCM: pentane (1: 1 v: v) followed by dichloromethane (2 × 1 mL) gave the title compound as an off-white solid (0.3 g, 55% yield). . ¹ H NMR (400 MHz, DMSO) δppm 10.13 (s, ¹ H), 9.84 (s, 1H), 7.31 (d, 1H), 7.09 (d, 1H), 3.58 (s, 4H), 1.74-1.45 ( m, 6H)

N-hydroxy-5-methanesulfonylthiophene-2-sulfonamide (83)
5-Methanesulfonylthiophene-2-sulfonyl chloride 2-Methanesulfonylthiophene (5 g, 30.82 mmol) was added to chlorosulfonic acid (14.37 mL, 215.74 mmol) and the resulting solution was heated to 90 ° C. for 1 hour. The solution was then cooled to about 25 ° C. and poured onto ice (250 mL). The resulting suspension was extracted into dichloromethane (3 × 100 mL) and the combined organic portions were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the desired compound as a light tan solid, It exists as a mixture with the corresponding 1,4 isomer and was directly used directly in the synthesis of the corresponding N-hydroxysulfonamide (4.6 g, 39% yield, 2,4 isomer and As a 1: 1 mixture). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ7.59 (d, J = 3.8Hz, 1H), 7.20 (d, J = 3.8Hz, 1H), 3.33 (s, 3H).

N-hydroxy-5-methanesulfonylthiophene-2-sulfonamide—To a solution of aqueous hydroxylamine (158% of a 50% solution, 158 mL, 23.97 mmol) in tetrahydrofuran (15 mL) and water (2.5 mL) cooled to −5 ° C. While maintaining the reaction temperature below 10 ° C., a 1: 1 mixture (2.5 g, 9.58 mmol) of 5-methanesulfonylthiophene-2-sulfonyl chloride and 5-methanesulfonylthiophene-3-sulfonyl chloride was slowly added. added. The reaction is maintained at this temperature until complete consumption of the sulfonyl chloride is observed by LC-MS (about 5 min), after which the reaction is diluted with dichloromethane (20 mL) and the organic portion is separated off. , Washed with water (2 × 5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a 1: 1 mixture of N-hydroxysulfonamide as a by-product with the corresponding 2,4 isomer. As obtained. The compound was then chromatographed by acidic HPLC and the two isomers were completely separated (0.58 g, 46% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ), title compound: δ10.09 (s, 2H), 7.91 (d, J = 4.0Hz, 1H), 7.75 (d, J = 4.0Hz, 1H), 3.48 ¹ H NMR (500 MHz, DMSO-d ₆ ), 2,4 isomers: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ9.84 (s, 1H), 9.77 (s, 1H), 8.65 (d, J = 1.6Hz, 1H), 7.99 (d, J = 1.6Hz, 1H), 3.46 (s, 4H).

Preparation of N-hydroxy-5-methylthiophene-2-sulfonamide (84) 5-Methylthiophene-2-sulfonyl chloride 5-Methylthiophene-2-sulfonyl chloride is prepared according to Sone et al., Bull. Chem. Soc. 58: 1063-1064 (1985). While maintaining the temperature below 25 ° C., freshly distilled sulfuryl chloride (74.9 mL, 0.93 mol) was added dropwise to ice-cold DMF (71.5 mL, 0.93 mol) with stirring. The hygroscopic solid complex formed after 10 minutes was held at the same temperature for an additional 30 minutes. To this complex was added 2-methylthiophene (70 g, 0.71 mol) and the mixture was heated at 98 ° C. for 1 hour. The viscous brown mixture was cooled, poured into ice water and extracted into diethyl ether (2 × 1 L). The organic layer was washed successively with water (500 mL), 5% NaHCO ₃ solution (200 mL) and water (500 mL), then dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the sulfonyl chloride as a dark brown Obtained as a liquid. The sulfonyl chloride was chromatographed on CC eluting with 0-30% EtOAc: heptane (110 g, 78% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δppm 7.69 (1H, d, J = 3.9Hz), 6.88-6.83 (1H, m), 2.60 (3H, d, J = 0.8Hz).

N-Hydroxy-5-methylthiophene-2-sulfonamide Reaction to a solution of aqueous hydroxylamine (8.4% 50% aqueous solution, 50.9 mmol) in THF (60 mL) and water (10 mL) cooled to −5 ° C. 5-Methylthiophene-2-sulfonyl chloride (10 g, 50.9 mmol) was added slowly while maintaining the temperature below 10 ° C. The reaction is maintained at this temperature until complete consumption of the sulfonyl chloride is observed by LC-MS (about 5 min), after which the reaction is diluted with DCM (100 mL) and the organic portion is separated. , Washed with water (2 × 25 mL). The aqueous extracts were combined and rewashed with DCM (2 × 75 mL). All organic portions were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give N-hydroxysulfonamide as a beige solid. Trituration with heptane gave the title compound as a beige solid (6.1 g, 61.8% yield). LC-MS t _R = 1.1 min; HRMS: Theoretical value (C ₅ H ₇ NO ₃ S ₂ ) = 191.9789, found value = 191.9781; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.71 (1H, d, J = 3.3Hz), 9.58 (1H, d, J = 3.5Hz), 7.46 (1H, d, J = 3.8Hz), 6.95 (1H, dd, J = 3.7, 1.0Hz), 2.53 (3H, s).

N-hydroxy-1-methyl-1H-pyrazole-3-sulfonamide (85)
To a solution of aqueous hydroxylamine (7.32 mL of 50% solution, 110.73 mmol) in tetrahydrofuran (48 mL) and water (8 mL) cooled to −5 ° C. while maintaining the reaction temperature below 10 ° C., 1-methyl -1H-pyrazole-3-sulfonyl chloride (8 g, 44.29 mmol) was added slowly. The reaction is maintained at this temperature until substantially complete consumption of the sulfonyl chloride is observed by TLC (about 5 minutes), after which the reaction is diluted with dichloromethane (50 mL) and the organic portion is separated. Washed with water (2 × 10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give N-hydroxysulfonamide as an off-white solid. Trituration with heptane: DCM (1: 1, v: v) gave the title compound as an off-white solid (4.3 g, 55% yield). _LC-MS t R = 0.41 ^{min, [M + H] + =} 179. ¹ H NMR (250 MHz, DMSO-d ₆ ) δppm 9.62 (d, J = 3.2Hz, 1H), 9.51 (d, J = 3.2Hz, 1H), 7.89 (d, J = 2.3Hz, 1H), 6.68 (d, J = 2.3Hz, 1H), 3.93 (s, 3H).

Preparation of 3-chloro-4-fluoro-N-hydroxybenzene-1-sulfonamide (87) Hydroxylamine (1.3 mL of 50% aqueous solution, 21. 21 mL) in THF (12 mL) and water (2 mL) cooled to 0 ° C. To a solution of 8 mmol) 3-chloro-4-fluorobenzene-1-sulfonyl chloride (2 g, 8.7 mmol) was added in small portions, keeping the temperature below 10 ° C. The reaction was stirred for 20 minutes, after which LC-MS showed complete consumption of the sulfonyl chloride. The reaction was diluted with diethyl ether (2 × 50 mL) and the organic portion was separated and washed with 5% citric acid solution (10 mL) and water (10 mL). The organic portion was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was triturated with diethyl ether: heptane to give the title compound as a white solid (1.14 g, 58% yield). LC-MS t _R = 1.54 min; HRMS: Theoretical (C ₆ H ₅ ClFNO ₃ S) = 223.9584, found = 223.963; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.79 (1H, d, 3.2Hz), 9.73 (1H, d, 3.2, Hz), 7.98 (1H, dd, 6.87Hz, 2.29, Hz), 7.85 (1H, m).

1-N, 3-N-dihydroxybenzene-1,3-disulfonamide (88)
To a solution of aqueous hydroxylamine (2.4 mL of a 50% solution, 36.35 mmol) in tetrahydrofuran (12 mL) and water (2 mL) cooled to −5 ° C. while maintaining the reaction temperature below 10 ° C. , 3-Disulfonyldichloride (2 g, 7.27 mmol) was added slowly. The reaction is maintained at this temperature until substantially complete consumption of the sulfonyl chloride is observed by TLC (about 5 minutes), after which the reaction is diluted with ethyl acetate (25 mL) and the organic portion is separated. And washed with water (2 × 10 mL) and ammonium chloride (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give N-hydroxysulfonamide as a white solid. Trituration with heptane gave the title compound as a white solid (0.567 g, 29% yield). Concentration to 1/3 volume of the filtrate gave a second batch of N-hydroxysulfonamide (0.327 g, 17% yield). LC-MS t _R = 0.87 min; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.88 (s, 2H), 9.82 (s, 2H), 8.28 (t, J = 1.7Hz, 1H) , 8.14 (dd, J = 7.9, 1.8Hz, 2H), 7.91 (t, J = 7.9Hz, 1H).

3-Bromo-N-hydroxybenzene-1-sulfonamide (89)
To an aqueous solution (2.4 mL) of hydroxylamine HCl (1.62 g, 23.48 mmol) cooled to 0 ° C., an aqueous solution (3.6 mL) of potassium carbonate (3.24 g, 23.48 mmol) and an internal reaction temperature of 5 It was added dropwise while maintaining between 15 ° C and 15 ° C. The reaction mixture was stirred for 15 minutes, at which point tetrahydrofuran (12 mL) and methanol (3.0 mL) were added. 3-Bromobenzenesulfonyl chloride (3.0 g, 11.74 mmol) is added in small portions while maintaining the temperature below 15 ° C., and then until complete complete consumption of the sulfonyl chloride is observed by TLC. The reaction mixture was stirred at a temperature of about 25 ° C. The resulting suspension was concentrated under reduced pressure to remove any volatiles and the aqueous suspension was extracted with diethyl ether (2 × 50 mL). The organic portion was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give N-hydroxysulfonamide as a white solid (1.8 g, 61% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δppm 9.75 (1H, d, J = 8.1Hz), 9.77 (1H, s), 7.92 (1H, d, J = 8.1Hz), 7.95 (1H, t, J = 1.7 Hz), 7.84 (1H, d, J = 7.8 Hz), 7.60 (1H, t, J = 7.9 Hz); predicted value [M−H] ⁻ = 249.9174; observed value [M−H] ^- = 249.9163.

Preparation of N-hydroxy-3- (trifluoromethoxy) benzene-1-sulfonamide (92) Hydroxylamine (6.4% 50% aqueous solution, 95.95%) in THF (60 mL) and water (10 mL) cooled to 0 ° C. 9) solution of 3- (trifluoromethoxy) benzene-1-sulfonyl chloride (10 g, 38.4 mmol) was added in portions, keeping the temperature below 10 ° C. The reaction was stirred for 20 minutes, after which LC-MS showed complete consumption of the sulfonyl chloride. The reaction was diluted with DCM (2 × 50 mL) and the organic portion was separated and washed with ammonium chloride solution (10 mL) and water (10 mL). The organic portion was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was triturated with heptane to give the title compound as a white solid (6.77 g, 66.6% yield). _LC-MS t R = 1.67 min; HRMS: theory _{(C 7 H 6 F 3 NO} 4 S) = 255.9891, measured ^{= 255.9903; 1 H NMR (250} MHz, DMSO-d 6) δppm 9.82 (2H, s), 7.89 (1H, dt, J = 7.3, 1.7Hz), 7.84-7.70 (3H, m).

N-hydroxy-4-methanesulfonylbenzene-1-sulfonamide (93)
To a solution of aqueous hydroxylamine (50% solution 6.48 mL, 98.15 mmol) in tetrahydrofuran (60 mL) and water (10 mL) cooled to −5 ° C. while maintaining the reaction temperature below 10 ° C., 4-methane Sulfonylbenzene-1-sulfonyl chloride (10 g, 39.26 mmol) was added slowly as a suspension in tetrahydrofuran (20 mL). The reaction is maintained at this temperature until complete consumption of the sulfonyl chloride is observed by LC-MS (about 10 min), after which the reaction is diluted with dichloromethane (150 mL) and the organic portion is separated. , Washed with water (2 × 25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give N-hydroxysulfonamide as an off-white solid. Trituration with heptane: DCM (9: 1 v: v) gave the title compound as an off-white solid (5.46 g, 55.4% yield). LC-MS t _R = 0.89 min, [M−H] ⁻ = 250; ¹ H NMR (500 MHz, DMSO-d ₆ ) δppm 9.89 (1H, d, J = 2.4 Hz), 9.85 (1H, d , J = 2.4Hz), 8.19 (2H, d, J = 8.4Hz), 8.08 (2H, d, J = 8.4Hz), 3.32 (3H, s).

  It will be apparent to one skilled in the art that particular embodiments of the disclosed subject matter may be directed to one or more of the embodiments set forth above and below.

  The present invention has been disclosed in some detail by way of illustration and example for clarity of understanding, but various changes may be made without departing from the true spirit and scope of the invention, and It will be apparent to those skilled in the art that equivalents can be substituted. Accordingly, the description and examples should not be construed as limiting the scope of the invention.

  All references, publications, patents and patent applications disclosed herein are hereby incorporated by reference in their entirety.

Claims (71)

  A method of treating heart failure comprising administering a nitroxyl donor composition to a human patient, said composition being 10 in pH 7.4 human plasma as measured by the procedure described in Example 2. A method comprising an N-hydroxysulfonamide type nitroxyl donor having a half-life greater than minutes and a cyclodextrin.   2. The N-hydroxysulfonamide type nitroxyl donor having a half-life of about 12 minutes to about 85 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. The method described in 1.   2. The N-hydroxysulfonamide type nitroxyl donor having a half-life of about 25 minutes to about 75 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. The method described in 1.   2. The method of claim 1, wherein the N-hydroxysulfonamide type nitroxyl donor has a half-life of less than 95 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. .   5. The cyclodextrin according to claim 1, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having 6 or 7 sulfo-n-butyl ether groups per molecule of cyclodextrin. Method.   The method according to any one of claims 1 to 4, wherein the cyclodextrin is CAPTISOL (registered trademark).   7. The molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.02: 1 to about 2: 1. The method according to claim 1.   The molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.05: 1 to about 1.5: 1. The method as described in any one of.   7. The molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.5: 1 to about 1: 1. The method according to claim 1.   10. The method according to any one of claims 1 to 9, wherein the composition is suitable for parenteral administration.   The method of claim 10, wherein the composition is suitable for intravenous administration.   12. The method of claim 10 or claim 11, wherein the composition is formulated at a pH of about 4 to about 6.   12. The method of claim 10 or claim 11, wherein the composition is formulated at a pH of about 5 to about 6.   12. The method of claim 10 or claim 11, wherein the composition is formulated at a pH of about 5.5 to about 6.   15. The method according to any one of claims 1 to 14, wherein the heart failure is acute decompensated heart failure. The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1)

The method according to claim 1, wherein: The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (2)

The method according to claim 1, wherein:   A method for treating heart failure, wherein a human patient has an N-hydroxysulfonamide type nitroxyl donor having a half-life of greater than 10 minutes as measured in human plasma at pH 7.4 by the procedure described in Example 2 Administering a nitroxyl donor composition comprising: wherein the composition is administered parenterally at a pH of about 5 to about 6.5.   The method of claim 18, wherein the composition is administered intravenously.   20. The method of claim 18 or claim 19, wherein the composition is administered at a pH of about 5.5 to about 6.   20. A method according to claim 18 or claim 19, wherein the composition is administered at a pH of about 6.   19. The N-hydroxysulfonamide type nitroxyl donor has a half-life of about 12 minutes to about 85 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. 22. The method according to any one of 21 to 21.   19. The N-hydroxysulfonamide type nitroxyl donor has a half-life of about 25 minutes to about 75 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. 22. The method according to any one of 21 to 21.   22. The N-hydroxysulfonamide type nitroxyl donor having a half-life of less than 95 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. The method according to claim 1.   25. A method according to any one of claims 18 to 24, wherein the composition further comprises a stabilizer.   26. The method of claim 25, wherein the stabilizer is a cyclodextrin.   27. The method of claim 26, wherein the cyclodextrin is [beta] -cyclodextrin. The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1)

28. A method according to any one of claims 18 to 27, wherein The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (2)

28. A method according to any one of claims 18 to 27, wherein   About 5 to about 6 comprising an N-hydroxysulfonamide type nitroxyl donor having a half-life greater than 10 minutes as measured in human plasma at pH 7.4 by the procedure described in Example 2 and an aqueous buffer. A pharmaceutical composition having a pH of   32. The pharmaceutical composition of claim 30, wherein the aqueous buffer provides the composition with a pH of about 5.5 to about 6.2.   32. The pharmaceutical composition of claim 30, wherein the aqueous buffer provides a pH of about 6 to the composition.   33. The pharmaceutical composition according to any one of claims 30 to 32, wherein the buffer is a phosphate or acetate buffer.   34. The pharmaceutical composition according to claim 33, wherein the buffer is a potassium phosphate buffer.   34. The pharmaceutical composition according to claim 33, wherein the buffer is a potassium acetate buffer.   36. The pharmaceutical composition according to any one of claims 30 to 35, further comprising a stabilizer.   37. A pharmaceutical composition according to claim 36, wherein the stabilizer is a cyclodextrin.   38. The pharmaceutical composition according to claim 37, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of [beta] -cyclodextrin having 6 or 7 sulfo-n-butyl ether groups per molecule of cyclodextrin.   39. A pharmaceutical composition according to claim 37 or claim 38, wherein the cyclodextrin is CAPTISOL (R).   40. Any of claims 37 to 39, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.02: 1 to about 2: 1. A pharmaceutical composition according to claim 1.   40. The molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.05: 1 to about 1.5: 1. Pharmaceutical composition as described in any one of these.   40. Any of claims 37 to 39, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.5: 1 to about 1: 1. A pharmaceutical composition according to claim 1.   31. The N-hydroxysulfonamide type nitroxyl donor has a half-life of about 12 minutes to about 85 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. 43. The pharmaceutical composition according to any one of to 42.   31. The N-hydroxysulfonamide type nitroxyl donor has a half-life of about 25 minutes to about 75 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. 43. The pharmaceutical composition according to any one of to 42.   43. Any of the claims 30-42, wherein the N-hydroxysulfonamide type nitroxyl donor has a half-life of less than 95 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. A pharmaceutical composition according to claim 1. The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1)

43. The pharmaceutical composition according to any one of claims 30 to 42, wherein The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (2)

43. The pharmaceutical composition according to any one of claims 30 to 42, wherein   (I) an N-hydroxysulfonamide type nitroxyl donor having a half-life of greater than 10 minutes as measured in human plasma at pH 7.4 by the procedure described in Example 2, and (ii) a medicament comprising cyclodextrin Composition.   49. The N-hydroxysulfonamide type nitroxyl donor has a half-life of about 12 minutes to about 85 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. A pharmaceutical composition according to 1.   49. The N-hydroxysulfonamide type nitroxyl donor has a half-life of about 25 minutes to about 75 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. A pharmaceutical composition according to 1.   49. The medicament of claim 48, wherein the N-hydroxysulfonamide type nitroxyl donor has a half-life of less than 95 minutes as measured in human plasma at pH 7.4 under the conditions specified in Example 2. Composition.   52. The cyclodextrin according to any one of claims 48 to 51, wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having 6 or 7 sulfo-n-butyl ether groups per cyclodextrin molecule. Pharmaceutical composition.   52. The pharmaceutical composition according to any one of claims 48 to 51, wherein the cyclodextrin is CAPTISOL (R).   54. Any of claims 48 to 53, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.02: 1 to about 2: 1. A pharmaceutical composition according to claim 1.   54. The molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.05: 1 to about 1.5: 1. Pharmaceutical composition as described in any one of these.   54. Any of claims 48-53, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.5: 1 to about 1: 1. A pharmaceutical composition according to claim 1. The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1)

54. The pharmaceutical composition according to any one of claims 48 to 53, wherein The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (2)

54. The pharmaceutical composition according to any one of claims 48 to 53, wherein   An N-hydroxysulfonamide type nitroxyl donor having a half-life of greater than 10 minutes as measured in human plasma at pH 7.4 by the procedure described in Example 2 and a cyclodextrin, present in the composition A mixture wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin is from about 0.02: 1 to about 2: 1.   60. The mixture of claim 59, formed by lyophilization.   60. The molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.05: 1 to about 1.5: 1. Item 60. The mixture according to Item 60.   62. The mixture of claim 61, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.5: 1 to about 1: 1. .   63. The mixture according to any one of claims 59 to 62, further comprising a buffering agent.   64. The mixture of claim 63, wherein the buffering agent is potassium acetate. The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1)

65. The mixture according to any one of claims 59 to 64, wherein The N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (2)

65. The mixture according to any one of claims 59 to 64, wherein   59. Use of a pharmaceutical composition according to any one of claims 30 to 58 for the manufacture of a medicament useful for treating cardiovascular disease.   59. Use of a pharmaceutical composition according to any one of claims 30 to 58 for the manufacture of a medicament useful for treating heart failure.   59. Use of a pharmaceutical composition according to any one of claims 30 to 58 for the manufacture of a medicament useful for the treatment of acute decompensated heart failure.   59. A pharmaceutical composition according to any one of claims 30 to 58 for use in the treatment of heart failure.   59. A pharmaceutical composition according to any one of claims 30 to 58 for use in the treatment of acute decompensated heart failure.

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